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http://www.ncbi.nlm.nih.gov/pubmed/24302690 | 1. Chem Senses. 2014 Feb;39(2):143-50. doi: 10.1093/chemse/bjt063. Epub 2013 Dec
3.
Pregnancy does not affect human olfactory detection thresholds.
Cameron EL(1).
Author information:
(1)Department of Psychological Science, Carthage College, 2001 Alford Park
Drive, Kenosha, WI 53140-1994, USA. lcameron@carthage.edu.
Hyperosmia is suspected in pregnancy; however, no empirical study using
validated measures of olfactory function has clearly confirmed the anecdotal
reports of this phenomenon. The goal of the current study is to compare the
olfactory sensitivity of pregnant women to that of nonpregnant women and men.
All participants rated their sense of smell and pregnant women listed the odors
to which they were most sensitive. Detection thresholds were measured using a
well-validated protocol. A group of pregnant and nonpregnant women was studied
longitudinally using a signal detection procedure designed to detect small
differences in sensitivity. Pregnant women, particularly in the 1st trimester,
rated their sense of smell to be higher than nonpregnant women and men and
indicated many (primarily unpleasant) odors to which they were more sensitive.
Women rated their sense of smell higher than men. However, there was no sex
difference in thresholds and neither thresholds nor signal detection measures of
sensitivity were significantly affected by either sex or pregnancy status. The
implications of the lack of relationship between self-report and measures of
olfactory sensitivity, particularly in pregnancy, are discussed.
DOI: 10.1093/chemse/bjt063
PMID: 24302690 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17100408 | 1. Drugs. 2006;66(15):1989-2001; discussion 2002-4. doi:
10.2165/00003495-200666150-00007.
Vildagliptin.
Henness S(1), Keam SJ.
Author information:
(1)Wolters Kluwer Health, Adis, Auckland, New Zealand. demail@adis.co.nz
Vildagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that is being
evaluated in the treatment of patients with type 2 diabetes mellitus. It
improves glycaemic control by inhibiting DPP-4 from inactivating the incretin
hormones glucagon-like peptide-1 and glucose-dependent insulinotropic
polypeptide, prolonging incretin activity in response to ingestion of nutrients.
This allows for increased insulin sensitivity, decreased glucagon secretion and
improved beta-cell function in a glucose-dependent manner. Glycaemic control
with vildagliptin 50 or 100 mg/day, measured by a change from baseline in mean
glycosylated haemoglobin (HbA(1c)) at study endpoint, was improved relative to
placebo in several well designed clinical trials of vildagliptin monotherapy in
patients with type 2 diabetes. In randomised active comparator studies,
noninferiority of vildagliptin in reducing HbA(1c) levels from baseline was
established to rosiglitazone, but not to metformin. Vildagliptin also showed
efficacy in reducing HbA(1c) levels in patients with type 2 diabetes when used
in combination with metformin, pioglitazone or insulin. Vildagliptin was
generally well tolerated when administered alone or in combination with
additional antidiabetic treatment. Gastrointestinal adverse events were mild to
moderate in intensity, and occurred less frequently than with metformin.
Hypoglycaemic events were rare and occurred at a similar incidence to that with
placebo.
DOI: 10.2165/00003495-200666150-00007
PMID: 17100408 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21913883 | 1. Recent Pat Endocr Metab Immune Drug Discov. 2011 Sep;5(3):197-202. doi:
10.2174/187221411797265926.
Linagliptin and newer DPP-4 inhibitors: newer uses and newer indications.
Kalra S(1), Unnikrishnan AG, Agrawal N, Singh AK.
Author information:
(1)Bharti Hospital, Karnal, Haryana, India. brideknl@gmail.com
The dipeptidyl peptidase-4 (DPP-4) inhibitors linagliptin, sitagliptin,
saxagliptin, vildagliptin and alogliptin are being developed and have been
approved for the treatment of type-2 diabetes. These agents may be used either
as monotherapy for the treatment of type-2 diabetes or in combination with other
anti-diabetic drugs. The present review highlights the use of linagliptin and
other new (DPP-4) inhibitors in the management of type-2 diabetes. The review
also highlights advantages, comparative pharmacokinetic, safety profile and
other potential uses including potential newer indications of DPP-4 inhibitors
and relevant patents. The other potential uses that are not restricted to
diabetes include obesity, cardiovascular disease, neurological disease,
hepatobiliary disease, wound healing, and other inflammatory illnesses.
DOI: 10.2174/187221411797265926
PMID: 21913883 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21250223 | 1. Cranial Nerve I: The Olfactory Nerve.
Walker HK.
In: Walker HK(1), Hall WD(1), Hurst JW(1), editors. Clinical Methods: The
History, Physical, and Laboratory Examinations. 3rd edition. Boston:
Butterworths; 1990. Chapter 59.
Author information:
(1)Emory University School of Medicine, Atlanta, Georgia
Hyperosmia is increased olfactory acuity, and hypoosmia is diminished olfactory
acuity. Anosmia, the inability to recognize odors, may be unilateral or
bilateral. Dysosmia is an abnormal sense of smell.
Copyright © 1990, Butterworth Publishers, a division of Reed Publishing.
PMID: 21250223 |
http://www.ncbi.nlm.nih.gov/pubmed/15825541 | 1. Can J Neurol Sci. 2005 Feb;32(1):4-17. doi: 10.1017/s0317167100016826.
Review of awakening agents.
DeMarchi R(1), Bansal V, Hung A, Wroblewski K, Dua H, Sockalingam S, Bhalerao S.
Author information:
(1)Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Brain injuries are a serious burden of illness to Canada and the US. Advances in
managing head trauma have allowed more patients to emerge from decreased levels
of consciousness and helped them cope with neurocognitive, neurobehavioural, and
neuropsychiatric deficits. In this article, we review the current (1986-2002)
evidence surrounding the pharmacological management of arousal states and the
aforementioned neurological sequelae of head injury in either acute or chronic
conditions. This article will review the evidence for the use of
psychostimulants (methylphenidate), antidepressants (amitriptyline, selective
serotonin reuptake inhibitors, and buproprion), Parkinson's medications
(amantadine, bromocriptine, carbidopa/levodopa), anticonvulsants (valproic
acid), modafinil (Provigil), lactate, hyperbaric oxygen chamber,
electroconvulsive therapy, and transmagnetic stimulation, in patients following
a head injury. The review did not include all anticonvulsants, neuroleptics,
beta-blockers, benzodiazepines, azospirones or cognitive enhancers.
Unfortunately, the quality of the evidence is generally poor, and sometimes
conflicting, which in turn results in indecisive guidelines for treating
patients. Accepting the inherent flaws in the evidence we feel that this paper
may serve as a stepping-stone for future researchers to improve data gathering
that targets neurocognitive, neurobehavioural and neuropsychiatric symptoms
following a head injury.
DOI: 10.1017/s0317167100016826
PMID: 15825541 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24246230 | 1. J Microbiol Methods. 2014 Jan;96:84-91. doi: 10.1016/j.mimet.2013.11.003. Epub
2013 Nov 15.
Analysis of the genetic distribution among members of Clostridium botulinum
group I using a novel multilocus sequence typing (MLST) assay.
Olsen JS(1), Scholz H(2), Fillo S(3), Ramisse V(4), Lista F(3), Trømborg AK(5),
Aarskaug T(5), Thrane I(5), Blatny JM(5).
Author information:
(1)Norwegian Defence Research Establishment, P.O. Box 25, N-2027 Kjeller,
Norway. Electronic address: Jaran-Strand.Olsen@ffi.no.
(2)German Armed Forces, Institute of Microbiology, Munich, Germany.
(3)Army Medical and Veterinary Research Center, Via Santo Stefano Rotondo 4,
I-00184 Rome, Italy.
(4)Division of Analytical Microbiology, DGA CBRN Defence, BP3, 91710 Vert le
Petit, France.
(5)Norwegian Defence Research Establishment, P.O. Box 25, N-2027 Kjeller,
Norway.
Clostridium botulinum is the etiological agent of botulism. Due to food-borne
poisoning and the potential use of the extremely toxic botulinum neurotoxin
(BoNT) from C. botulinum in bioterror or biocrime related actions, reliable high
resolution typing methods for discriminating C. botulinum strains are needed.
Partial sequencing of the adk, atpH, gyrB, proC, rpoD and spo0A genes from 51
various C. botulinum/sporogenes isolates was performed, resulting in 37
different sequence types (STs). Analysis of the sequence data revealed a genetic
distribution in five larger clusters with a loose correlation to the BoNT
serotypes. The developed MLST assay had a slightly lower resolution ability when
compared to the MLVA (multilocus variable number of tandem repeat analysis), but
the two methods resulted in similar subclusters of the strains possessing the
BoNT serotypes A, B and F. The current work presents the development of a novel
MLST assay useful for genotyping C. botulinum related to basic phylogenetic
research and trace-back analysis in microbial forensic studies.
Copyright © 2013 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.mimet.2013.11.003
PMID: 24246230 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23126680 | 1. Cell Biosci. 2012 Nov 6;2(1):37. doi: 10.1186/2045-3701-2-37.
Strategies to identify long noncoding RNAs involved in gene regulation.
Lee C(1), Kikyo N.
Author information:
(1)Stem Cell Institute, Department of Genetics, Cell Biology and Development,
University of Minnesota, Room 2-216, MTRF, 2001 6th St, SE, Minneapolis, MN,
55455, USA. kikyo001@umn.edu.
Long noncoding RNAs (lncRNAs) have been detected in nearly every cell type and
found to be fundamentally involved in many biological processes. The
characterization of lncRNAs has immense potential to advance our comprehensive
understanding of cellular processes and gene regulation, along with implications
for the treatment of human disease. The recent ENCODE (Encyclopedia of DNA
Elements) study reported 9,640 lncRNA loci in the human genome, which
corresponds to around half the number of protein-coding genes. Because of this
sheer number and their functional diversity, it is crucial to identify a pool of
potentially relevant lncRNAs early on in a given study. In this review, we
evaluate the methods for isolating lncRNAs by immunoprecipitation and review the
advantages, disadvantages, and applications of three widely used approaches -
microarray, tiling array, and RNA-seq - for identifying lncRNAs involved in gene
regulation. We also look at ways in which data from publicly available databases
such as ENCODE can support the study of lncRNAs.
DOI: 10.1186/2045-3701-2-37
PMCID: PMC3499186
PMID: 23126680 |
http://www.ncbi.nlm.nih.gov/pubmed/23369519 | 1. BMC Med Genomics. 2013;6 Suppl 1(Suppl 1):S7. doi: 10.1186/1755-8794-6-S1-S7.
Epub 2013 Jan 23.
Potential roles of microRNAs in regulating long intergenic noncoding RNAs.
Juan L(1), Wang G, Radovich M, Schneider BP, Clare SE, Wang Y, Liu Y.
Author information:
(1)Center for Biomedical Informatics, Harbin Institute of Technology School of
Computer Science and Technology, Harbin, Heilongjiang 150001, China.
BACKGROUND: Over 10,000 long intergenic non-coding RNAs (lincRNAs) have been
identified in the human genome. Some have been well characterized and known to
participate in various stages of gene regulation. In the post-transcriptional
process, another class of well-known small non-coding RNA, or microRNA (miRNA),
is very active in inhibiting mRNA. Though similar features between mRNA and
lincRNA have been revealed in several recent studies, and a few isolated
miRNA-lincRNA relationships have been observed. Despite these advances, the
comprehensive miRNA regulation pattern of lincRNA has not been clarified.
METHODS: In this study, we investigated the possible interaction between the two
classes of non-coding RNAs. Instead of using the existing long non-coding
database, we employed an ab initio method to annotate lincRNAs expressed in a
group of normal breast tissues and breast tumors.
RESULTS: Approximately 90 lincRNAs show strong reverse expression correlation
with miRNAs, which have at least one predicted target site presented. These
target sites are statistically more conserved than their neighboring genetic
regions and other predicted target sites. Several miRNAs that target to these
lincRNAs are known to play an essential role in breast cancer.
CONCLUSION: Similar to inhibiting mRNAs, miRNAs show potential in promoting the
degeneration of lincRNAs. Breast-cancer-related miRNAs may influence their
target lincRNAs resulting in differential expression in normal and malignant
breast tissues. This implies the miRNA regulation of lincRNAs may be involved in
the regulatory process in tumor cells.
DOI: 10.1186/1755-8794-6-S1-S7
PMCID: PMC3552696
PMID: 23369519 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24567800 | 1. World J Diabetes. 2014 Feb 15;5(1):40-51. doi: 10.4239/wjd.v5.i1.40.
Insulin plus incretin: A glucose-lowering strategy for type 2-diabetes.
Ahrén B(1).
Author information:
(1)Bo Ahrén, Department of Clinical Sciences Lund, Lund University, 221 84 Lund,
Sweden.
There are many advantages of combining incretin therapy [glucagon-like peptide-1
(GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors] with
insulin therapy as a glucose-lowering strategy in type 2 diabetes. One important
advantage is the complementary mode of the mechanistic action of incretin and
insulin therapy. Another advantage is the reduction in risk of hypoglycemia and
weight gain when adding incretin therapy to insulin. Several clinical trials
have studied the addition of GLP-1 receptor agonists [exenatide BID (twice
daily), lixisenatide, albiglutide] or DPP-4 inhibitors (vildagliptin,
sitagliptin, saxagliptin, alogliptin, linagliptin) to ongoing insulin therapy or
adding insulin to ongoing therapy with a GLP-1 receptor agonist (liraglutide).
These studies show improved glycemia in the presence of limited risk for
hypoglycemia and weight gain with the combination of incretin therapy with
insulin. This article reviews the background and clinical studies on this
combination.
DOI: 10.4239/wjd.v5.i1.40
PMCID: PMC3932426
PMID: 24567800 |
http://www.ncbi.nlm.nih.gov/pubmed/26087627 | 1. Ter Arkh. 2015;87(4):8-12. doi: 10.17116/terarkh20158748-12.
[Assessment of the role of matrix metalloproteinase-3 gene polymorphism in the
development of chronic heart failure].
[Article in Russian; Abstract available in Russian from the publisher]
Teplyakov AT(1), Berezikova EN(2), Shilov SN(2), Grakova EV(1), Torim YY(1),
Efremov AV(2), Safronov ID(2), Pustovetova MG(2), Karpov RS(1).
Author information:
(1)Department of Heart Failure, Research Institute of Cardiology, Tomsk, Russia.
(2)Novosibirsk State Medical University, Ministry of Health of Russia,
Novosibirsk, Russia.
AIM: To study the impact of a polymorphic variant of the matrix
metalloproteinase-3 (MMP-3) gene on the development and course of chronic heart
failure (CHF) in patients with coronary heart disease.
SUBJECTS AND METHODS: A total of 277 patients with New York Heart Association
(NYHA) Functional Class (FC) II-IV CHF were examined. MMP-3 -1171 5A/6A genetic
polymorphism was studied by polymerase chain reaction. A control group included
136 patients (mean age 53.6 ± 4.8 years) with no signs of cardiovascular
diseases, as evidenced by the examination.
RESULTS: The frequency of the 5A allele and the 5A/5A genotype of the 1171 5A/6A
polymorphic locus in the MMP-3 gene proved to be higher in the patients with CHF
than that in the control group. Thus, the variability of the 5A allele (odds
ratio (OR), 1.39; 95% confidence interval (CI): 1.033 to 1.869; p = 0.03) and
the 5A/5A genotype (OR, 2.15; 95% CI: 1.131 to 4.070; p = 0.02) was associated
with increased risk for CHF. There were significant differences in the frequency
of MMP-3 alleles and genotypes in relation to FC of CHF. The frequency of the
5A/5A genotype was substantially higher in the patients with NYHA FC IV CHF than
that in those with NYHA FC II CHF (32.8% versus 15.2%; p = 0.039). The frequency
of the 5A allele was significantly higher in the patients with NYHA FC IV CHF
than that in those with NYHA FC II CHF (55.5% and 39.3%; respectively; p =
0.019). Thus, the carriage of the 5A allele and the 5A/5A genotype of the 1171
5A/6A polymorphic locus in the MMP-3 gene is a risk factor of severe CHF.
CONCLUSION: The determination of MMP-3 -1171 5A/6A polymorphism may be
recommended for the early prediction of a risk for the development and severe
course of CHF.
Publisher: Цель исследования. Изучить влияние полиморфного варианта гена
матриксной металлопротеиназы-3 (ММР-3) на развитие и течение хронической
сердечной недостаточности (ХСН) у больных ишемической болезнью сердца. Материалы
и методы. Обследовали 277 человек с ХСН II-IV функционального класса (ФК) по
классификации Нью-Йоркской ассоциации кардиологов (NYHA). Исследовали
генетический полиморфизм –1171 5A/6A гена ММР-3 с помощью полимеразной цепной
реакции. В группу контроля вошли 136 человек (средний возраст 53,6±4,8 года), не
имевших по данным обследования признаков сердечно-сосудистых заболеваний.
Результаты. Частота аллеля 5А и генотипа 5А/5А полиморфного локуса 1171 5A/6A
гена ММР-3 у пациентов с ХСН оказалась выше, чем в группе контроля. Таким
образом, вариабельность аллеля 5А (отношение шансов - ОШ 1,39 при 95%
доверительном интервале - ДИ от 1,033 до 1,869; p=0,03) и генотипа 5А/5А (OШ
2,15 при 95%и ДИ от 1,131 до 4,070; p=0,02) ассоциировалась с повышенным риском
развития ХСН. Установлены достоверные различия по частоте аллелей и генотипов
гена ММР-3 в зависимости от ФК ХСН. Частота генотипа 5А/5А у больных с ХСН IV ФК
по классификации NYHA была существенно выше, чем при ХСН II ФК (32,8% против
15,2%; р=0,039). Частота аллеля 5А у пациентов с IV ФК ХСН оказалась выше, чем у
пациентов с ХСН II ФК (55,5 и 39,3% соответственно; р=0,019). Таким образом,
носительство аллеля 5А и генотипа 5А/5А полиморфного локуса 1171 5A/6A гена
ММР-3 является фактором риска тяжелого течения ХСН. Заключение. Определение
полиморфизма –1171 5A/6A гена ММР-3 может быть рекомендовано для раннего
прогнозирования риска развития и тяжести течения ХСН.
DOI: 10.17116/terarkh20158748-12
PMID: 26087627 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24252701 | 1. Vaccine. 2014 Jan 3;32(2):214-6. doi: 10.1016/j.vaccine.2013.11.025. Epub 2013
Nov 16.
Vaccination of cattle with a recombinant bivalent toxoid against botulism
serotypes C and D.
Cunha CE(1), Moreira GM(1), Salvarani FM(2), Neves MS(2), Lobato FC(2),
Dellagostin OA(1), Conceição FR(3).
Author information:
(1)Centro de Desenvolvimento Tecnológico, Núcleo de Biotecnologia, Universidade
Federal de Pelotas, CP 354, CEP 96010-900 Pelotas, RS, Brazil.
(2)Escola de Veterinária, Universidade Federal de Minas Gerais, CP 567, CEP
30123-970 Belo Horizonte, MG, Brazil.
(3)Centro de Desenvolvimento Tecnológico, Núcleo de Biotecnologia, Universidade
Federal de Pelotas, CP 354, CEP 96010-900 Pelotas, RS, Brazil. Electronic
address: fabricio.rochedo@ufpel.edu.br.
Cattle botulism is a fatal intoxication caused by botulinum neurotoxins (BoNTs)
produced by Clostridium botulinum serotypes C and D resulting in economic
losses. Vaccination is the most effective way to control botulism. However, the
commercially available vaccines are difficult and hazardous to produce.
Neutralizing antibodies against the C-terminal fragment of the BoNT heavy chain
(HC) are known to protect against lethal doses of BoNTs. We report the
vaccination of cattle with a previously tested recombinant chimera consisting of
Escherichia coli heat-labile enterotoxin B subunit and the HC of BoNTs C and D.
Vaccinated animals produced neutralizing antibodies against serotypes C and D
averaging 5±0 and 6.14±1.06IU/mL, respectively. For BoNT D, the titers were
greater than those measured for the commercial vaccine, which induced titers of
5±0 and 2.85±1.35 against the respective serotypes, suggesting that this chimera
is effective against cattle botulism.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.vaccine.2013.11.025
PMID: 24252701 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15839401 | 1. Crit Rev Microbiol. 2005;31(1):11-8. doi: 10.1080/10408410590912952.
Clostridium botulinum: a bug with beauty and weapon.
Shukla HD(1), Sharma SK.
Author information:
(1)Center of Marine Biotechnology, University of Maryland Biotechnology
Institute, Baltimore, Maryland 21202, USA. shukla@umbi.umd.edu
Clostridium botulinum, a Gram-positive, anaerobic spore-forming bacteria, is
distinguished by its significant clinical applications as well as its potential
to be used as bioterror agent. Growing cells secrete botulinum neurotoxin
(BoNT), the most poisonous of all known poisons. While BoNT is the causative
agent of deadly neuroparalytic botulism, it also serves as a remarkably
effective treatment for involuntary muscle disorders such as blepharospasm,
strabismus, hemifacial spasm, certain types of spasticity in children, and other
ailments. BoNT is also used in cosmetology for the treatment of glabellar lines,
and is well-known as the active component of the anti-aging medications Botox
and Dysport. In addition, recent reports show that botulinum neurotoxin can be
used as a tool for pharmaceutical drug delivery. However, BoNT remains the
deadliest of all toxins, and is viewed by biodefense researchers as a possible
agent of bioterrorism (BT). Among seven serotypes, C. botulinum type A is
responsible for the highest mortality rate in botulism, and thus has the
greatest potential to act as biological weapon. Genome sequencing of C.
botulinum type A Hall strain (ATCC 3502) is now complete, and has shown the
genome size to be 3.89 Mb with a G+C content of approximately 28.2%. The
bacterium harbors a 16.3 kb plasmid with a 26.8% G+C content--slightly lower
than that of the chromosome. Most of the virulence factors in C. botulinum are
chromosomally encoded; bioinformatic analysis of the genome sequence has shown
that the plasmid does not harbor toxin genes or genes for related virulence
factors. Interestingly, the plasmid does harbor genes essential to replication,
including dnaE, which encodes the alpha subunit of DNA polymerase III which has
close similarity with its counterpart in C. perfringens strain 13. The plasmid
also contains similar genes to those that encode the ABC-type multidrug
transport ATPase, and permease. The presence of ABC-type multidrug transport
ATPase, and permease suggests putative involvement of efflux pumps in
bacteriocin production, modification, and export in C. botulinum. The C.
botulinum plasmid additionally harbors genes for LambdaBa04 prophage and
site-specific recombinase that are similar to those found in the Ames strain of
Bacillus anthracis; these genes and their products may play a role in genomic
rearrangement. Completion of genome sequencing for C. botulinum will provide an
opportunity to design genomic and proteomic-based systems for detecting
different serotypes of C. botulinum strains in the environment. The completed
sequence may also facilitate identification of potential virulence factors and
drug targets, as well as help characterize neurotoxin-complexing proteins, their
polycistronic expression, and phylogenetic relationships between different
serotypes.
DOI: 10.1080/10408410590912952
PMID: 15839401 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11153358 | 1. Hautarzt. 2000 Oct;51(10):733-7. doi: 10.1007/s001050051206.
[Botulinum toxin: from poison to drug. A historical review].
[Article in German]
Kreyden OP(1), Geiges ML, Böni R, Burg G.
Author information:
(1)Dermatologische Klinik des Universitätsspitals Zürich, Gloriastrasse 31, 8091
Zürich, Schweiz. kreyden.derm.unizh.ch
Botulinumtoxin (BTX) is a neurotoxin produced from Clostridium botulinum under
anaerobic conditions and is responsible for botulism, a notifiable, bacterial
form of food poisoning. The first case of botulism is believed to have occurred
in 1735. An epidemic in Southern Germany in 1793 claimed the death of over the
half of those patients who had become ill through eating uncooked blood
sausages. The term "pharmakon" is Greek and implicates that a drug originates
from poison (potion, remedy). Theophrastus Bombast von Hohenheim known as
Paracelsus (1493/94-1541) first described this duality with his dictum "alle
ding sind gift und nichts on gift; alein die dosis macht das ein ding kein gift
ist" (only the dose makes a remedy poisonous). In Baden-Württemberg in 1817, the
poet and physician Dr. Justinus Christian Kerner described the symptoms of
botulism, so that at this time botulism was also called Kerner disease. Until
the turn of the century the reason for poisoning was not known. Van Ermengem
succeeded in isolating the anaerobic bacterium causing botulism, but the
specific mechanism of BTX was only established after the second World War. In
the late seventies the ophthalmologist Dr. Alan Scott used BTX the first time in
the treatment of strabismus. The drug was then used in the treatment of several
muscle spasticities such as, for example, torticollis or hemifacial spasm. Only
recently BTX has been successfully used for focal hyperhidrosis. We review the
history of botulinum toxin from its discovery in the nineteenth century and the
research into its effect in the middle of the 20th century up to its clinical
use at the present time.
DOI: 10.1007/s001050051206
PMID: 11153358 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24025056 | 1. Curr Pharm Des. 2014;20(26):4140-53.
Disorders of consciousness and pharmaceuticals that act on oxygen based amino
acid and monoamine neurotransmitter pathways of the brain.
Clauss R(1).
Author information:
(1)Nuclear Medicine Department, Royal Surrey County Hospital, Guildford, Surrey,
GU27XX, United Kingdom. rclauss@nhs.net.
Oxygen based neurotransmitters in the synapses of the brain are proposed to play
an important role in the generation of consciousness. They include the amino
acids glutamate and GABA which use Krebs cycle precursors for their synthesis,
and the monoamines dopamine, noradrenalin, adrenalin and serotonin, which are
derived from tyrosine and tryptophan. During ischemia after an acute brain
injury, a GABA surge often initiates brain suppression. It has been proposed
that with chronic ischemia, a secondary, possibly epigenetic response occurs
when neurotransmitters deplete, a glucose and oxygen saving mechanism termed
neurodormancy that may invoke alternative long term low energy metabolic
pathways in the brain, encountered in Disorders of Consciousness. Some
medications can reverse Disorders of Consciousness in some patients. Virtually
all of them act on neurotransmitter systems that use oxygen as a building block
or as an energy source within the brain. Pharmaceuticals that act in the oxygen
based amino acid systems of the brain include the GABAergic medications zolpidem
and baclofen, while those that act in the monoamine axes include the
dopaminergic medications L Dopa, amantadine, bromocriptine, apomorphine and
methylphenidate, and the noradrenergic and serotonergic medications desipramine,
amitriptyline, protriptyline and fluoxetine. Another group are the
cholinesterase inhibitors, responsible for increasing acetylcholine, which is
synthesized from the Krebs cycle initiator, acetyl CoA. It appears that
pharmaceuticals that are active in the oxygen based neurotransmitter pathways of
the brain are successful to arouse to consciousness patients that suffer from
its disorders. Research needs to be supported as foundation to understand the
biochemical mechanisms that are involved in consciousness disorders and to
explore further the pharmacological treatment possibilities for these
devastating neurological conditions.
PMID: 24025056 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24206405 | 1. Arch Iran Med. 2013 Nov;16(11):642-6.
Identification of botulinum toxin type in clinical samples and foods in Iran.
Shahcheraghi F(1), Nobari S, Masoumi Asl H, Aslani MM.
Author information:
(1)Department of Bacteriology and Microbiology Research Center, Pasteur
Institute of Iran, Tehran, Iran. shahcheraghifereshteh@yahoo.com.
BACKGROUND: Botulism is a serious neuroparalytic disease caused by toxins of
Clostridium botulinum. Botulinum toxin is produced under anaerobic conditions
and is one of the most dangerous toxin in the world. Rapid diagnosis of botulism
is very essential for successful therapy. In this study, we reviewed data of
cases of botulism in Iran from April 2004 through March 2010.
MATHERIALS AND METHODS: From a total of 1140 samples of suspected botulism
samples, 477 serum, 294 stool, 111 gastric secretions, and 258 food samples were
collected from 21 provinces. These samples belonged to 432 distinct patients.
All samples were tested for botulism by mouse bioassay, a gold standard method
for detection of botulism.
RESULTS: From 1140 received samples, 64 (5.6 %) positive samples of botulism
were identified. Of these, 14 (21.8 %) cases had toxin type A, seven (11 %)
cases had toxin type B, 22 (34.3 %) cases had toxin type E, and seven (11 %)
cases had toxin type AB. The toxin type could not been identified in 14 (21.8 %)
cases. The highest positive results were in Gilan, Tehran, Golestan, and Hamedan
provinces. Seafoods and locally- made cheese were the most implicated foods in
type E and type A botulism, respectively.
CONCLUSION: Accurate and rapid diagnosis of botulism is very important because
every case of botulism can be a public health emergency. During the study
period, the median number of positive cases per year was 2.7 (range: one to18).
Therefore, it is suggested that all clinicians are required to submit the
collected samples from patients with botulism symptoms to the botulism reference
laboratory for specific diagnosis and confirmation of botulism.
PMID: 24206405 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23846593 | 1. Database (Oxford). 2013 Jul 11;2013:bat034. doi: 10.1093/database/bat034.
Print 2013.
lncRNome: a comprehensive knowledgebase of human long noncoding RNAs.
Bhartiya D(1), Pal K, Ghosh S, Kapoor S, Jalali S, Panwar B, Jain S, Sati S,
Sengupta S, Sachidanandan C, Raghava GP, Sivasubbu S, Scaria V.
Author information:
(1)GN Ramachandran Knowledge Center for Genome Informatics, CSIR Institute of
Genomics and Integrative Biology, Mall Road, Delhi 110007, India.
The advent of high-throughput genome scale technologies has enabled us to
unravel a large amount of the previously unknown transcriptionally active
regions of the genome. Recent genome-wide studies have provided annotations of a
large repertoire of various classes of noncoding transcripts. Long noncoding
RNAs (lncRNAs) form a major proportion of these novel annotated noncoding
transcripts, and presently known to be involved in a number of functionally
distinct biological processes. Over 18,000 transcripts are presently annotated
as lncRNA, and encompass previously annotated classes of noncoding transcripts
including large intergenic noncoding RNA, antisense RNA and processed
pseudogenes. There is a significant gap in the resources providing a stable
annotation, cross-referencing and biologically relevant information. lncRNome
has been envisioned with the aim of filling this gap by integrating annotations
on a wide variety of biologically significant information into a comprehensive
knowledgebase. To the best of our knowledge, lncRNome is one of the largest and
most comprehensive resources for lncRNAs. Database URL:
http://genome.igib.res.in/lncRNome.
DOI: 10.1093/database/bat034
PMCID: PMC3708617
PMID: 23846593 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20961439 | 1. BMC Microbiol. 2010 Oct 20;10:267. doi: 10.1186/1471-2180-10-267.
Universal and specific quantitative detection of botulinum neurotoxin genes.
Hill BJ(1), Skerry JC, Smith TJ, Arnon SS, Douek DC.
Author information:
(1)Human Immunology Section, Vaccine Research Center, National Institutes of
Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
20892, USA.
BACKGROUND: Clostridium botulinum, an obligate anaerobic spore-forming
bacterium, produces seven antigenic variants of botulinum toxin that are
distinguished serologically and termed "serotypes". Botulinum toxin blocks the
release of acetylcholine at neuromuscular junctions resulting in flaccid
paralysis. The potential lethality of the disease warrants a fast and accurate
means of diagnosing suspected instances of food contamination or human
intoxication. Currently, the Food and Drug Administration (FDA)-accepted assay
to detect and type botulinum neurotoxins (BoNTs) is the mouse protection
bioassay. While specific and sensitive, this assay requires the use of
laboratory animals, may take up to four days to achieve a diagnosis, and is
unsuitable for high-throughput analysis. We report here a two-step PCR assay
that identifies all toxin types, that achieves the specificity of the mouse
bioassay while surpassing it in equivalent sensitivity, that has capability for
high-throughput analysis, and that provides quantitative results within hours.
The first step of our assay consists of a conventional PCR that detects the
presence of C. botulinum regardless of the neurotoxin type. The second step uses
quantitative PCR (qPCR) technology to determine the specific serotype of the
neurotoxin.
RESULTS: We assayed purified C. botulinum DNA and crude toxin preparations, as
well as food and stool from healthy individuals spiked with purified BoNT DNA,
and one stool sample from a case of infant botulism for the presence of the NTNH
gene, which is part of the BoNT gene cluster, and for the presence of
serotype-specific BoNT genes. The PCR surpassed the mouse bioassay both in
specificity and sensitivity, detecting positive signals in BoNT preparations
containing well below the 1 LD50 required for detection via the mouse bioassay.
These results were type-specific and we were reliably able to quantify as few as
10 genomic copies.
CONCLUSIONS: While other studies have reported conventional or quantitative
PCR-based assays for the detection of C. botulinum genes, our procedure's
high-throughput capability and its portability allows most laboratories to
quickly assess the possible presence of BoNTs either in food processing samples
or in suspected cases of botulism. Thus, this assay provides rapid and specific
detection of BoNT and toxin complex genes and would enable the targeting of
appropriate therapeutics to infected individuals in a timely manner.
DOI: 10.1186/1471-2180-10-267
PMCID: PMC2973968
PMID: 20961439 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24961027 | 1. J Egypt Soc Parasitol. 2014 Apr;44(1):211-20. doi: 10.12816/0006461.
Botulism as a food poisoning: what is it?
El-Bahnasawy MM, Aly NZ, Abdel-Fattah MA, Morsy TA.
Botulism is a rare but potentially life-threatening neuroparalytic syndrome
resulting from the action of a neurotoxin elaborated by the microorganism
Clostridium botulinum. This disease has a lengthy history; the first
investigation of botulism occurred in the 1820s with a case report on hundreds
of patients with "sausage poisoning" in a southern German town. Several decades
later in Belgium, the association was demonstrated between a neuromuscular
paralysis and ham infected by a spore forming bacillus that was isolated from
the ham. The organism was named Bacillus botulinus after the Latin word for
sausage, botulus.
DOI: 10.12816/0006461
PMID: 24961027 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20460949 | 1. Stereotact Funct Neurosurg. 2010;88(4):199-207. doi: 10.1159/000314354. Epub
2010 May 12.
Vegetative state and minimally conscious state: a review of the therapeutic
interventions.
Georgiopoulos M(1), Katsakiori P, Kefalopoulou Z, Ellul J, Chroni E,
Constantoyannis C.
Author information:
(1)Functional Neurosurgery Unit, Department of Neurosurgery, Medical School of
Patras, Patras, Greece.
BACKGROUND/AIMS: The purpose of the present article is a systematic review of
the proposed medical or surgical treatments in patients in chronic vegetative
state (VS) or minimally conscious state (MCS), as well as of their mechanisms of
action and limitations.
METHODS: For this review, we have agreed to include patients in VS or MCS having
persisted for over 6 months in posttraumatic cases, and over 3 months in
nontraumatic cases, before the time of intervention. Searches were independently
conducted by 2 investigators between May 2009 and September 2009 in the
following databases: Medline, Web of Science and the Cochrane Library. The
electronic search was complemented by cross-checking the references of all
relevant articles. Overall, 16 papers were eligible for this systematic review.
RESULTS: According to the 16 eligible studies, medical management by
dopaminergic agents (levodopa, amantadine), zolpidem and median nerve
stimulation, or surgical management by deep brain stimulation, extradural
cortical stimulation, spinal cord stimulation and intrathecal baclofen have
shown to improve the level of consciousness in certain cases.
CONCLUSION: The treatments proposed for disorders of consciousness have not yet
gained the level of 'evidence-based treatments'; moreover, the studies to date
have led to inconclusiveness. The published therapeutic responses must be
substantiated by further clinical studies of sound methodology.
2010 S. Karger AG, Basel.
DOI: 10.1159/000314354
PMID: 20460949 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21855841 | 1. Am J Hum Genet. 2011 Sep 9;89(3):415-23. doi: 10.1016/j.ajhg.2011.07.014.
Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause
a recessive hypomyelinating leukodystrophy.
Bernard G(1), Chouery E, Putorti ML, Tétreault M, Takanohashi A, Carosso G,
Clément I, Boespflug-Tanguy O, Rodriguez D, Delague V, Abou Ghoch J, Jalkh N,
Dorboz I, Fribourg S, Teichmann M, Megarbane A, Schiffmann R, Vanderver A, Brais
B.
Author information:
(1)Departments of Pediatrics, Neurology and Neurosurgery, Division of Pediatric
Neurology, Montreal Children's Hospital, McGill University Heath Center,
Montreal, Quebec, Canada. bernard.brais@mcgill.ca
Erratum in
Am J Hum Genet. 2012 Nov 2;91(5):972.
Leukodystrophies are a heterogeneous group of inherited neurodegenerative
disorders characterized by abnormal white matter visible by brain imaging. It is
estimated that at least 30% to 40% of individuals remain without a precise
diagnosis despite extensive investigations. We mapped tremor-ataxia with central
hypomyelination (TACH) to 10q22.3-23.1 in French-Canadian families and sequenced
candidate genes within this interval. Two missense and one insertion mutations
in five individuals with TACH were uncovered in POLR3A, which codes for the
largest subunit of RNA polymerase III (Pol III). Because these families were
mapped to the same locus as leukodystrophy with oligodontia (LO) and presented
clinical and radiological overlap with individuals with hypomyelination,
hypodontia and hypogonadotropic hypogonadism (4H) syndrome, we sequenced this
gene in nine individuals with 4H and eight with LO. In total, 14 recessive
mutations were found in 19 individuals with TACH, 4H, or LO, establishing that
these leukodystrophies are allelic. No individual was found to carry two
nonsense mutations. Immunoblots on 4H fibroblasts and on the autopsied brain of
an individual diagnosed with 4H documented a significant decrease in POLR3A
levels, and there was a more significant decrease in the cerebral white matter
compared to that in the cortex. Pol III has a wide set of target RNA
transcripts, including all nuclear-coded tRNA. We hypothesize that the decrease
in POLR3A leads to dysregulation of the expression of certain Pol III targets
and thereby perturbs cytoplasmic protein synthesis. This type of broad
alteration in protein synthesis is predicted to occur in other
leukoencephalopathies such as hypomyelinating leukodystrophy-3, caused by
mutations in aminoacyl-tRNA synthetase complex-interacting multifunctional
protein 1 (AIMP1).
Copyright © 2011 The American Society of Human Genetics. Published by Elsevier
Inc. All rights reserved.
DOI: 10.1016/j.ajhg.2011.07.014
PMCID: PMC3169829
PMID: 21855841 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22257051 | 1. Curr Med Chem. 2012;19(7):1036-64. doi: 10.2174/092986712799320628.
MMP-2 selectivity in hydroxamate-type inhibitors.
Serra P(1), Bruczko M, Zapico JM, Puckowska A, Garcia MA, Martin-Santamaria S,
Ramos A, de Pascual-Teresa B.
Author information:
(1)Department of Chemistry, Universidad CEU San Pablo, Madrid, Spain.
Extracellular matrix metalloproteinases (MMPs) are a family of zinc-dependent
neutral endopeptidases involved in physiological and pathological processes,
through the cleavage of extracellular matrix. MMPs are capable of degrading
essentially all matrix components, which is crucial for malignant tumor growth,
invasion, metastasis and angiogenesis. The vertebrates MMP family includes at
least 26 enzymes (23 have been known in humans) with only MMP-1, 2, and 7
experimentally validated as targets for antitumoral drug design. However,
inhibition of MMP-1 has been hypothesized to be the cause of the clinically
observed musculoskeletal syndrome when broad spectrum inhibitors are used. On
the other hand, MMP-9 is a tricky enzyme, since its inhibition might be useful
in treating patients with early-stage cancers, but MMP-9 is an anti-target in
patients with advanced disease. So, MMP-9 inhibition should also be prevented.
Therefore, selective MMP-2 inhibition arises as a pursued profile for MMP
binders. Among them, hydroxamates have been extensively studied as small
molecule drug candidates characterized by an effective zinc-binding group plus
additional side chains responsible for the selectivity. This article pays
particular attention to MMP-2 selectivity on hydroxamate-type inhibitors,
especially against MMP-9, and their chemical structure, SAR, general synthetic
methods, and molecular modelling studies are here reviewed in order to inspire
further design of new effective anticancer agents.
DOI: 10.2174/092986712799320628
PMID: 22257051 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8474442 | 1. Mol Cell Biol. 1993 May;13(5):2802-14. doi: 10.1128/mcb.13.5.2802-2814.1993.
(CT)n (GA)n repeats and heat shock elements have distinct roles in chromatin
structure and transcriptional activation of the Drosophila hsp26 gene.
Lu Q(1), Wallrath LL, Granok H, Elgin SC.
Author information:
(1)Department of Biology, Washington University, St. Louis, Missouri 63130.
Previous analysis of the hsp26 gene of Drosophila melanogaster has shown that in
addition to the TATA box and the proximal and distal heat shock elements (HSEs)
(centered at -59 and -340, relative to the start site of transcription), a
segment of (CT)n repeats at -135 to -85 is required for full heat shock
inducibility (R.L. Glaser, G.H. Thomas, E.S. Siegfried, S.C.R. Elgin, and J.T.
Lis, J. Mol. Biol. 211:751-761, 1990). This (CT)n element appears to contribute
to formation of the wild-type chromatin structure of hsp26, an organized
nucleosome array that leaves the HSEs in nucleosome-free, DNase I-hypersensitive
(DH) sites (Q. Lu, L.L. Wallrath, B.D. Allan, R.L. Glaser, J.T. Lis, and S.C.R.
Elgin, J. Mol. Biol. 225:985-998, 1992). Inspection of the sequences upstream of
hsp26 has revealed an additional (CT)n element at -347 to -341, adjacent to the
distal HSE. We have analyzed the contribution of this distal (CT)n element (-347
to -341), the proximal (CT)n element (-135 to -85), and the two HSEs both to the
formation of the chromatin structure and to heat shock inducibility. hsp26
constructs containing site-directed mutations, deletions, substitutions, or
rearrangements of these sequence elements have been fused in frame to the
Escherichia coli lacZ gene and reintroduced into the D. melanogaster genome by
P-element-mediated germ line transformation. Chromatin structure of the
transgenes was analyzed (prior to gene activation) by DNase I or restriction
enzyme treatment of isolated nuclei, and heat-inducible expression was monitored
by measuring beta-galactosidase activity. The results indicate that mutations,
deletions, or substitutions of either the distal or the proximal (CT)n element
affect the chromatin structure and heat-inducible expression of the transgenes.
These (CT)n repeats are associated with a nonhistone protein(s) in vivo and are
bound by a purified Drosophila protein, the GAGA factor, in vitro. In contrast,
the HSEs are required for heat-inducible expression but play only a minor role
in establishing the chromatin structure of the transgenes. Previous analysis
indicates that prior to heat shock, these HSEs appear to be free of protein. Our
results suggest that GAGA factor, an abundant protein factor required for normal
expression of many Drosophila genes, and heat shock factor, a specific
transcription factor activated upon heat shock, play distinct roles in gene
regulation: the GAGA factor establishes and/or maintains the DH sites prior to
heat shock induction, while the activated heat shock factor recognizes and binds
HSEs located within the DH sites to trigger transcription.
DOI: 10.1128/mcb.13.5.2802-2814.1993
PMCID: PMC359663
PMID: 8474442 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11158316 | 1. Mol Cell Biol. 2001 Feb;21(4):1311-8. doi: 10.1128/MCB.21.4.1311-1318.2001.
The iab-7 polycomb response element maps to a nucleosome-free region of
chromatin and requires both GAGA and pleiohomeotic for silencing activity.
Mishra RK(1), Mihaly J, Barges S, Spierer A, Karch F, Hagstrom K, Schweinsberg
SE, Schedl P.
Author information:
(1)Département de Zoologie et Biologie Animale, Université de Genève, 1211
Geneva 4, Switzerland.
In the work reported here we have undertaken a functional dissection of a
Polycomb response element (PRE) from the iab-7 cis-regulatory domain of the
Drosophila melanogaster bithorax complex (BX-C). Previous studies mapped the
iab-7 PRE to an 860-bp fragment located just distal to the Fab-7 boundary.
Located within this fragment is an approximately 230-bp chromatin-specific
nuclease-hypersensitive region called HS3. We have shown that HS3 is capable of
functioning as a Polycomb-dependent silencer in vivo, inducing pairing-dependent
silencing of a mini-white reporter. The HS3 sequence contains consensus binding
sites for the GAGA factor, a protein implicated in the formation of
nucleosome-free regions of chromatin, and Pleiohomeotic (Pho), a Polycomb group
protein that is related to the mammalian transcription factor YY1. We show that
GAGA and Pho interact with these sequences in vitro and that the consensus
binding sites for the two proteins are critical for the silencing activity of
the iab-7 PRE in vivo.
DOI: 10.1128/MCB.21.4.1311-1318.2001
PMCID: PMC99583
PMID: 11158316 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23520356 | 1. J Health Psychol. 2014 Jul;19(7):897-906. doi: 10.1177/1359105313481080. Epub
2013 Mar 21.
Experiences of environmental odors among self-reported hyperosmics: a pilot
study.
Knaapila A(1), Tuorila H(2).
Author information:
(1)University of Helsinki, Finland University of Turku, Finland.
(2)University of Helsinki, Finland hely.tuorila@helsinki.fi.
We investigated everyday odor experiences in 55 people (14-75 years old) who
rated their sense of smell as far better than average. Compared to 55 gender-
and age-matched controls, the self-reported hyperosmics scored higher on the
Affective Impact of Odor Scale, rated negative consequences and unpleasant
memories due to odors as more likely, rated environmental odors as more
annoying, reported increased sensitivity to specific odors more frequently, paid
more attention to odors, and agreed more strongly that their sense of smell has
caused inconvenience to them. Based on these data, subjective hyperosmia is
associated with primarily negative odor-related experiences.
© The Author(s) 2013.
DOI: 10.1177/1359105313481080
PMID: 23520356 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23239346 | 1. Curr Top Microbiol Immunol. 2013;364:1-20. doi: 10.1007/978-3-642-33570-9_1.
Genetic diversity within Clostridium botulinum serotypes, botulinum neurotoxin
gene clusters and toxin subtypes.
Hill KK(1), Smith TJ.
Author information:
(1)Los Alamos National Laboratory, Los Alamos, NM 87545, USA. khill@lanl.gov
Clostridium botulinum is a species of spore-forming anaerobic bacteria defined
by the expression of any one or two of seven serologically distinct botulinum
neurotoxins (BoNTs) designated BoNT/A-G. This Gram-positive bacterium was first
identified in 1897 and since then the paralyzing and lethal effects of its toxin
have resulted in the recognition of different forms of the intoxication known as
food-borne, infant, or wound botulism. Early microbiological and biochemical
characterization of C. botulinum isolates revealed that the bacteria within the
species had different characteristics and expressed different toxin types. To
organize the variable bacterial traits within the species, Group I-IV
designations were created. Interestingly, it was observed that isolates within
different Groups could express the same toxin type and conversely a single Group
could express different toxin types. This discordant phylogeny between the toxin
and the host bacteria indicated that horizontal gene transfer of the toxin was
responsible for the variation observed within the species. The recent
availability of multiple C. botulinum genomic sequences has offered the ability
to bioinformatically analyze the locations of the bont genes, the composition of
their toxin gene clusters, and the genes flanking these regions to understand
their variation. Comparison of the genomic sequences representing multiple
serotypes indicates that the bont genes are not in random locations. Instead the
analyses revealed specific regions where the toxin genes occur within the
genomes representing serotype A, B, C, E, and F C. botulinum strains and C.
butyricum type E strains. The genomic analyses have provided evidence of
horizontal gene transfer, site-specific insertion, and recombination events.
These events have contributed to the variation observed among the neurotoxins,
the toxin gene clusters and the bacteria that contain them, and has supported
the historical microbiological, and biochemical characterization of the Group
classification within the species.
DOI: 10.1007/978-3-642-33570-9_1
PMID: 23239346 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23421373 | 1. Environ Sci Technol. 2013 Mar 19;47(6):2587-94. doi: 10.1021/es304743m. Epub
2013 Mar 4.
Association of toxin-producing Clostridium botulinum with the macroalga
Cladophora in the Great Lakes.
Chun CL(1), Ochsner U, Byappanahalli MN, Whitman RL, Tepp WH, Lin G, Johnson EA,
Peller J, Sadowsky MJ.
Author information:
(1)BioTechnology Institute, University of Minnesota , St. Paul, Minnesota 55108,
USA.
Avian botulism, a paralytic disease of birds, often occurs on a yearly cycle and
is increasingly becoming more common in the Great Lakes. Outbreaks are caused by
bird ingestion of neurotoxins produced by Clostridium botulinum, a
spore-forming, gram-positive, anaerobe. The nuisance, macrophytic, green alga
Cladophora (Chlorophyta; mostly Cladophora glomerata L.) is a potential habitat
for the growth of C. botulinum. A high incidence of botulism in shoreline birds
at Sleeping Bear Dunes National Lakeshore (SLBE) in Lake Michigan coincides with
increasingly massive accumulations of Cladophora in nearshore waters. In this
study, free-floating algal mats were collected from SLBE and other shorelines of
the Great Lakes between June and October 2011. The abundance of C. botulinum in
algal mats was quantified and the type of botulism neurotoxin (bont) genes
associated with this organism were determined by using most-probable-number PCR
(MPN-PCR) and five distinct bont gene-specific primers (A, B, C, E, and F). The
MPN-PCR results showed that 16 of 22 (73%) algal mats from the SLBE and 23 of
31(74%) algal mats from other shorelines of the Great Lakes contained the bont
type E (bont/E) gene. C. botulinum was present up to 15000 MPN per gram dried
algae based on gene copies of bont/E. In addition, genes for bont/A and bont/B,
which are commonly associated with human diseases, were detected in a few algal
samples. Moreover, C. botulinum was present as vegetative cells rather than as
dormant spores in Cladophora mats. Mouse toxin assays done using supernatants
from enrichment of Cladophora containing high densities of C. botulinum (>1000
MPN/g dried algae) showed that Cladophora-borne C. botulinum were
toxin-producing species (BoNT/E). Our results indicate that Cladophora provides
a habitat for C. botulinum, warranting additional studies to better understand
the relationship between this bacterium and the alga, and how this interaction
potentially contributes to botulism outbreaks in birds.
DOI: 10.1021/es304743m
PMID: 23421373 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10845458 | 1. Plant Cell Physiol. 2000 Apr;41(4):448-57. doi: 10.1093/pcp/41.4.448.
A tobacco NtMET1 cDNA encoding a DNA methyltransferase: molecular
characterization and abnormal phenotypes of transgenic tobacco plants.
Nakano Y(1), Steward N, Sekine M, Kusano T, Sano H.
Author information:
(1)Research and Education Center for Genetic Information, Nara Institute of
Science and Technology, Ikoma, Japan.
A cDNA encoding a DNA methyltransferase, with a predicted polypeptide of 1556
amino acid residues containing all motifs conserved in this enzyme family, was
isolated from tobacco plants, and the corresponding gene was designated as
NtMET1. RNA blot analysis indicated NtMET1 transcripts to accumulate in dividing
tissues of tobacco plants, and they could be detected during the S phase in
synchronized dividing BY2 cells. In situ hybridization revealed the transcripts
to be localized exclusively in actively proliferating tissues around axillary
apical meristem. In order to ascertain physiological roles, transgenic tobacco
plants that had the antisense construct were made and examined for phenotypes.
Methylation levels of genomic DNA from transgenic plants significantly decreased
in comparison with wild-type levels, and distinct phenotypic changes including
small leaves, short internodes and abnormal flower morphology were noted.
Microscopic observation revealed that leaf structure differed between transgenic
and wild-type plants. These results suggest that NtMET1 functions during DNA
replication, and that DNA methylation plays an important role in plant
morphogenesis.
DOI: 10.1093/pcp/41.4.448
PMID: 10845458 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7737124 | 1. EMBO J. 1995 Apr 18;14(8):1727-36. doi: 10.1002/j.1460-2075.1995.tb07162.x.
Chromatin remodeling by GAGA factor and heat shock factor at the hypersensitive
Drosophila hsp26 promoter in vitro.
Wall G(1), Varga-Weisz PD, Sandaltzopoulos R, Becker PB.
Author information:
(1)European Molecular Biology Laboratory, Gene Expression Programme, Heidelberg,
Germany.
The chromatin structure at the Drosophila hsp26 promoter in vivo is
characterized by two DNase I-hypersensitive (DH) sites harboring regulatory
elements. Proximal and distal DH sites are separated by a positioned nucleosome.
To study the contribution of transcription factors to the establishment of this
specific chromatin configuration we assembled nucleosomes on the hsp26 promoter
using a cell-free reconstitution system derived from fly embryos. Both DH sites
were readily reconstituted from extract components. They were separated by a
nucleosome which was less strictly positioned than its in vivo counterpart. The
interactions of GAGA factor and heat shock factor with their binding sites in
chromatin occurred in two modes. Their interaction with binding sites in the
nucleosome-free regions did not require ATP. In the presence of ATP both factors
interacted also with nucleosomal binding sites, causing nucleosome
rearrangements and a refinement of nucleosome positions. While chromatin
remodeling upon transcription factor interaction has previously been interpreted
to involve nucleosome disruption, the data suggest energy-dependent nucleosome
sliding as main principle of chromatin reorganization.
DOI: 10.1002/j.1460-2075.1995.tb07162.x
PMCID: PMC398266
PMID: 7737124 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21171846 | 1. Clin Toxicol (Phila). 2010 Nov;48(9):880-95. doi:
10.3109/15563650.2010.526943.
Type E botulism.
Horowitz BZ(1).
Author information:
(1)Oregon - Alaska Poison Center, Oregon Health & Science University, Portland,
Oregon 97239, USA. horowiza@ohsu.edu
There are seven known serotypes of botulism, designated A through G; almost all
human cases of botulism are caused by types A, B, and E. Botulism type E is the
predominant serotype causing disease associated with native Arctic foods. In the
circumpolar regions of the world, the coastal soils are rich in botulism type E,
and consumption of fish and marine animals in these areas are the sources of
clusters of botulism. Unlike spores of type A and B, botulism type E can
withstand freezing down to 3.5°C. Alaskan native fermentation of fish heads,
fish eggs, and beaver tail allow proper anaerobic conditions for botulinum toxin
to be elaborated from Clostridium botulinum. The consumption of whale meat,
"muktuk" has also been associated with outbreaks of botulism in Alaska and the
Canadian Arctic. Elsewhere in the Arctic regions, type E botulism has been
associated with Norwegian "rakfisk" prepared by a process similar to fermented
Alaskan foods. Outbreaks in Egypt with the salted gray mullet "faseikh", in
Israel and New York linked to salted uneviscerated whitefish "kapchunka", in
Iran from eating "ashbal" an uncooked salmon, and in Japan with "izushi" a
traditional fermented fish preserved in rice have occurred. Importation of
vacuum-packed whitefish from Alaska and Canada has also been associated with
sporadic cases of botulism type E in Europe. In March 2010, the Center for
Disease Control and Prevention released the heptavalent antitoxin (H-BAT) for
use in the USA, under an Investigational New Drug program, as the preferred
treatment for food-borne botulism, including type E, which had not been covered
by the bivalent antitoxin, the prior approved antitoxin product in the USA.
DOI: 10.3109/15563650.2010.526943
PMID: 21171846 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21937732 | 1. Cold Spring Harb Perspect Biol. 2012 Jan 1;4(1):a004903. doi:
10.1101/cshperspect.a004903.
Overview of the matrisome--an inventory of extracellular matrix constituents and
functions.
Hynes RO(1), Naba A.
Author information:
(1)Howard Hughes Medical Institute, Koch Institute for Integrative Cancer
Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139,
USA. rohynes@mit.edu
Completion of genome sequences for many organisms allows a reasonably complete
definition of the complement of extracellular matrix (ECM) proteins. In mammals
this "core matrisome" comprises ∼300 proteins. In addition there are large
numbers of ECM-modifying enzymes, ECM-binding growth factors, and other
ECM-associated proteins. These different categories of ECM and ECM-associated
proteins cooperate to assemble and remodel extracellular matrices and bind to
cells through ECM receptors. Together with receptors for ECM-bound growth
factors, they provide multiple inputs into cells to control survival,
proliferation, differentiation, shape, polarity, and motility of cells. The
evolution of ECM proteins was key in the transition to multicellularity, the
arrangement of cells into tissue layers, and the elaboration of novel structures
during vertebrate evolution. This key role of ECM is reflected in the diversity
of ECM proteins and the modular domain structures of ECM proteins both allow
their multiple interactions and, during evolution, development of novel protein
architectures.
DOI: 10.1101/cshperspect.a004903
PMCID: PMC3249625
PMID: 21937732 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10655499 | 1. Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1148-53. doi:
10.1073/pnas.97.3.1148.
Early disruption of centromeric chromatin organization in centromere protein A
(Cenpa) null mice.
Howman EV(1), Fowler KJ, Newson AJ, Redward S, MacDonald AC, Kalitsis P, Choo
KH.
Author information:
(1)The Murdoch Institute, Royal Children's Hospital, Flemington Road, Parkville
3052, Australia.
Centromere protein A (Cenpa for mouse, CENP-A for other species) is a histone
H3-like protein that is thought to be involved in the nucleosomal packaging of
centromeric DNA. Using gene targeting, we have disrupted the mouse Cenpa gene
and demonstrated that the gene is essential. Heterozygous mice are healthy and
fertile whereas null mutants fail to survive beyond 6.5 days postconception.
Affected embryos show severe mitotic problems, including micronuclei and
macronuclei formation, nuclear bridging and blebbing, and chromatin
fragmentation and hypercondensation. Immunofluorescence analysis of interphase
cells at day 5.5 reveals complete Cenpa depletion, diffuse Cenpb foci, absence
of discrete Cenpc signal on centromeres, and dispersion of Cenpb and Cenpc
throughout the nucleus. These results suggest that Cenpa is essential for
kinetochore targeting of Cenpc and plays an early role in organizing centromeric
chromatin at interphase. The evidence is consistent with the proposal of a
critical epigenetic function for CENP-A in marking a chromosomal region for
centromere formation.
DOI: 10.1073/pnas.97.3.1148
PMCID: PMC15551
PMID: 10655499 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24252222 | 1. Vet J. 2014 Jan;199(1):157-61. doi: 10.1016/j.tvjl.2013.10.023. Epub 2013 Oct
26.
Quantitative real-time PCR for detection of neurotoxin genes of Clostridium
botulinum types A, B and C in equine samples.
Johnson AL(1), McAdams-Gallagher SC(2), Sweeney RW(2).
Author information:
(1)Department of Clinical Studies, New Bolton Center, University of Pennsylvania
School of Veterinary Medicine, Kennett Square, PA 19348, USA. Electronic
address: amyjohn@vet.upenn.edu.
(2)Department of Clinical Studies, New Bolton Center, University of Pennsylvania
School of Veterinary Medicine, Kennett Square, PA 19348, USA.
Botulism in horses in the USA is attributed to Clostridium botulinum types A, B
or C. In this study, a duplex quantitative real-time PCR (qPCR) for detection of
the neurotoxin genes of C. botulinum types A and B, and a singleplex qPCR for
detection of the neurotoxin gene of C. botulinum type C, were optimized and
validated for equine gastrointestinal, faecal and feed samples. The performance
of these assays was evaluated and compared to the standard mouse bioassay (MBA)
using 148 well-characterized samples, most of which were acquired from a
repository of veterinary diagnostic samples from cases of botulism: 106 samples
positive for C. botulinum (25 type A, 27 type B, 28 type C, 1 type D and 25 type
E) and 42 negative samples. The sensitivities of the qPCR assays were 89%, 86%
and 96% for C. botulinum types A, B and C, respectively. The overall sensitivity
of the mouse bioassay for types A, B and C was 81%. The specificities of the
qPCR assays were 99-100% and the specificity of the mouse bioassay was 95%.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tvjl.2013.10.023
PMID: 24252222 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18640997 | 1. J Exp Bot. 2008;59(12):3271-81. doi: 10.1093/jxb/ern178. Epub 2008 Jul 17.
Isolation and expression analysis of genes encoding MET, CMT, and DRM
methyltransferases in oil palm (Elaeis guineensis Jacq.) in relation to the
'mantled' somaclonal variation.
Rival A(1), Jaligot E, Beulé T, Finnegan EJ.
Author information:
(1)CIRAD, IRD, UMR DIAPC, BP 64501, F-34394 Montpellier, Cedex 5, France.
alain.rival@cirad.fr
In oil palm (Elaeis guineensis Jacq.), approximately 5% of somatic
embryo-derived regenerants show homeotic changes during floral development,
involving an apparent feminization of male parts in flowers of both sexes,
called the 'mantled' phenotype. This variant phenotype is associated with a
reduction in the level of global DNA methylation. To explore possible
relationships between DNA methylation level and accumulation of DNA-(cytosine-5)
methyltransferase (DNMT) transcripts, the full-length coding sequences
corresponding to three different DNMT families in oil palm, namely the MET, CMT,
and DRM classes, have been isolated and characterized. The corresponding genes
were designated as EgMET1, EgCMT1, and EgDRM1, and encode predicted polypeptides
of 1543, 925, and 591 amino acid residues, respectively. Expression of oil palm
DNMTs was compared between normal and variant calli and inflorescence tissues
using quantitative reverse-transcription PCR. A consistent increase in
transcript levels of EgMET1 and EgCMT1 was found in variant fast-growing calli
relative to nodular-compact calli. Nodular-compact calli give rise to about 5%
of abnormal regenerants whereas fast-growing calli generate 95% of 'mantled'
palms in their clonal offspring and were previously demonstrated as having
markedly hypomethylated DNA. In immature abnormal inflorescences only EgMET1
transcript levels were increased, while no changes in relative abundance of the
EgCMT1 or EgDRM1 transcripts were observed. Therefore, the genome-wide
hypomethylation previously described in 'mantled' material cannot be explained
by a decrease in expression levels of the de novo or maintenance DNMTs, a
paradox which has been previously reported in tumour cells, where there is
evidence for global hypomethylation of DNA.
DOI: 10.1093/jxb/ern178
PMID: 18640997 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24997242 | 1. Anaerobe. 2014 Aug;28:220-5. doi: 10.1016/j.anaerobe.2014.06.010. Epub 2014
Jul 2.
Chronic botulism in a Saxony dairy farm: sources, predisposing factors,
development of the disease and treatment possibilities.
Krüger M(1), Neuhaus J(1), Herrenthey AG(1), Gökce MM(1), Schrödl W(1), Shehata
AA(2).
Author information:
(1)Institute of Bacteriology and Mycology, Faculty of Veterinary Medicine,
Leipzig University, Germany.
(2)Institute of Bacteriology and Mycology, Faculty of Veterinary Medicine,
Leipzig University, Germany; Avian and Rabbit Diseases Department, Faculty of
Veterinary Medicine, Sadat City University, Egypt. Electronic address:
shehata@vetmed.uni-leipzig.de.
The aim of this study is to investigate Clostridium botulinum at a Saxony dairy
farm with 159 cows and 18 heifers. The animals exhibited clinical symptoms of
chronic botulism. To determine the source of the infection, feces, blood,
organs, and gastrointestinal fluids of dead or euthanized cows; as well as soil,
water, silage and manure were tested for C. botulinum spores and BoNTs using
ELISA. BoNT/C and C. botulinum type C were detected in 53% and 3% of tested
animals, respectively, while BoNT/D and C. botulinum type D were detected in 18%
of the animals. C. botulinum also was detected in organs, gastrointestinal
fluids, drinking water and manure. To evaluate possible treatments, animals were
given Jerusalem artichoke syrup (JAS), Botulism vaccine (formalinised aluminum
hydroxide gel adsorbed toxoid of C. botulinum types C and D) or a suspension of
Enterococcus faecalis. After four weeks treatment with JAS, BoNT/C and
C. botulinum type C were not detected in feces. In contrast, BoNT/D and
C. botulinum type D were not significantly influenced by the JAS treatment.
Vaccination with botulism vaccine and the E. faecalis suspension significantly
decreased BoNT/D and C. botulinum type D. A significant increase of Enterococci
was detected in animals treated with E. faecalis. Interestingly, there was a
negative correlation between the detection of both BoNT and C. botulinum with
the concentration of Enterococci in feces. Although C. botulinum C and D
antibodies increased significantly (p < 0.0001) after vaccination with the
botulism vaccine, the reduction of C. botulinum and BoNT in feces did not result
in recovery of the animals because they were deficient of trace elements
[manganese (Mn), cobalt (Co), copper (Cu) and selenium (Se)]. Animals treated
with trace elements recovered. It appears that intestinal microbiota dysbiosis
and trace element deficiency could explain the extensive emergence of chronic
Botulism.
Copyright © 2014 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.anaerobe.2014.06.010
PMID: 24997242 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16314512 | 1. Mol Cell Biol. 2005 Dec;25(24):10875-94. doi:
10.1128/MCB.25.24.10875-10894.2005.
Forkhead box M1 regulates the transcriptional network of genes essential for
mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase.
Wang IC(1), Chen YJ, Hughes D, Petrovic V, Major ML, Park HJ, Tan Y, Ackerson T,
Costa RH.
Author information:
(1)Department of Biochemistry and Molecular Genetics, University of Illinois at
Chicago, College of Medicine, 60607-7170, USA.
The Forkhead box m1 (Foxm1) gene is critical for G(1)/S transition and essential
for mitotic progression. However, the transcriptional mechanisms downstream of
FoxM1 that control these cell cycle events remain to be determined. Here, we
show that both early-passage Foxm1(-)(/)(-) mouse embryonic fibroblasts (MEFs)
and human osteosarcoma U2OS cells depleted of FoxM1 protein by small interfering
RNA fail to grow in culture due to a mitotic block and accumulate nuclear levels
of cyclin-dependent kinase inhibitor (CDKI) proteins p21(Cip1) and p27(Kip1).
Using quantitative chromatin immunoprecipitation and expression assays, we show
that FoxM1 is essential for transcription of the mitotic regulatory genes
Cdc25B, Aurora B kinase, survivin, centromere protein A (CENPA), and CENPB. We
also identify the mechanism by which FoxM1 deficiency causes elevated nuclear
levels of the CDKI proteins p21(Cip1) and p27(Kip1). We provide evidence that
FoxM1 is essential for transcription of Skp2 and Cks1, which are specificity
subunits of the Skp1-Cullin 1-F-box (SCF) ubiquitin ligase complex that targets
these CDKI proteins for degradation during the G(1)/S transition. Moreover,
early-passage Foxm1(-)(/)(-) MEFs display premature senescence as evidenced by
high expression of the senescence-associated beta-galactosidase, p19(ARF), and
p16(INK4A) proteins. Taken together, these results demonstrate that FoxM1
regulates transcription of cell cycle genes critical for progression into
S-phase and mitosis.
DOI: 10.1128/MCB.25.24.10875-10894.2005
PMCID: PMC1316960
PMID: 16314512 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9465302 | 1. Genomics. 1998 Jan 1;47(1):108-14. doi: 10.1006/geno.1997.5109.
Gene structure and sequence analysis of mouse centromere proteins A and C.
Kalitsis P(1), MacDonald AC, Newson AJ, Hudson DF, Choo KH.
Author information:
(1)Murdoch Institute for Research into Birth Defects, Royal Children's Hospital,
Melbourne, Australia.
We have determined the genomic structure and organization of the mouse Cenpa and
Cenpc genes. CENPA is a member of the histone H3-like proteins and is thought to
replace histone H3 in centromeric nucleosomes. CENPC is a DNA-binding protein
that is located at the inner kinetochore plate of active mammalian centromeres.
The Cenpa cDNA encodes a 134-amino-acid product that is 70% identical and 84%
similar to its human homolog. The mouse Cenpa gene is approximately 8 kb in
length and contains five exons. Sequence analysis of the 5' DNA sequence of the
gene revealed two consensus CAAT boxes, a putative TFIID-binding site, an
Sp1-binding domain, and two cell cycle regulatory motifs, but no consensus TATA
element. The mouse Cenpc gene spans 60 kb and contains 19 exons that range in
size from 44 to 602 bp. Sequence analysis of the C+G-rich promoter region showed
the presence of known promoter elements, including a CpG island, a CAAT box, and
several GC boxes, but the absence of a consensus TATA element.
DOI: 10.1006/geno.1997.5109
PMID: 9465302 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18671210 | 1. Rev Neurol. 2008 Aug 16-31;47(4):204-8.
[Central hypomyelination, hypogonadotrophic hypogonadism and hypodontia: a new
leukodystrophy].
[Article in Spanish]
Vázquez-López M(1), Ruiz-Martín Y, de Castro-Castro P, Garzo-Fernández C,
Martín-del Valle F, Márquez-de la Plata L.
Author information:
(1)Sección de Neuropediatría, Hospital Materno Infantil Gregorio Marañón,
Madrid, España. vazquezlopezmaria@gmail.com
AIM: To report one patient with slowly progressive encephalopathy, ataxia,
central hypomyelination, hypodontia and hypogonadotropic hypogonadism, the 4H
syndrome. This clinical picture has been described recently and there are only
four patients reported previously.
CASE REPORT: A girl with a previously normal early psychomotor development,
presented a slowly progressive deterioration since 15 months of age. Now, she is
14 years old, and has a severe cerebellar ataxia, with tremor and dysmetria. She
can't neither walk nor remain standing alone. She has lost the sphincter control
and has an immature expressive language. She has no puberal development and
definitive hypodontia of upper central incisors. The brain magnetic resonance
imaging shows a diffuse hypomyelination, that is confirmed with diffusion and
spectroscopy studies.
CONCLUSION: The hypomyelinating leukoencephalopathies are disorders with
abnormally low amount of myelin. The diagnosis is difficult in most of the
patients. The hypomyelinating leukoencephalopathies include classic disorders
and new leukoencephalopathies, described in the past few years.
PMID: 18671210 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23307887 | 1. J Child Neurol. 2014 Jan;29(1):135-8. doi: 10.1177/0883073812470737. Epub 2013
Jan 9.
An Indian boy with a novel leukodystrophy: 4H syndrome.
Jauhari P(1), Sahu JK, Singhi P, Dayal D, Khandelwal N.
Author information:
(1)1Pediatric Neurology Division, Department of Pediatrics, Post Graduate
Institute of Medical Education & Research, Chandigarh, India.
4H syndrome is a rare and distinct leukodystrophy characterized by
hypomyelination, hypogonadotropic hypogonadism, and hypodontia. Detecting signs
of pubertal growth failure and abnormal dentition offer the clues to the
diagnosis. We present an Indian boy with this novel syndrome with previously
unreported feature of bilateral undescended testes. We also provide a brief
overview of all published cases.
DOI: 10.1177/0883073812470737
PMID: 23307887 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21747146 | 1. Brain Nerve. 2011 Jul;63(7):755-61.
[Clostridium botulinum and botulinum neurotoxin].
[Article in Japanese]
Hirai Y(1).
Author information:
(1)Division of Bacteriology, Department of Infection and Immunity, Jichi Medical
School, Tochigi, Japan.
Clostridium botulinum is a gram-positive anaerobic rod that forms endospores.
This bacterium produces large molecular toxin complexes, namely botulinum toxin
complexes (progenitor toxins). It (L toxin complex) is composed of a single
neurotoxin molecule (BoNT with a molecular weight of 150 kDa), a single nontoxic
nonhemagglutinin molecule (NTNHA), and a hemagglutinin complex (HA). On
food-borne botulism, nontoxic components have the roles of protecting toxin
protein from the degeneration and degradation action of acids and proteases
existing in the gastrointestinal tract. The HA facilitates transport when
progenitor toxins cross the intestinal epithelial barrier to enter the systemic
circulation. BoNT disassociates from the toxin complexes in the systemic
circulation. BoNT is immunologically classified into 7 serotypes, A to G.
Serotypes A, B, E, and F are the causative agents of human botulism. The active
BoNT molecules are composed of 2 chains that are termed the heavy chain (c. 100
kDa) and the light chain (c. 50 kDa); these are covalently connected by a
disulfide bond. The light chains have a tetrahedral zinc binding motif
conteining a consensus HExxH amino acid sequence, and exhibit metalloprotease
activity. After BoNTs reach the neuromuscular junction (the peripheral nerve
ending), these are endocytosed in lipid vesicles (synaptic vesicles), and the
light chain is released into the cytosol of a nerve cell via a translocation
event through the phospholipid vesicle membrane. The light chains of BoNTs (zinc
endopeptidases) cleave core proteins involved in the trafficking and release of
neurotransmitters (acetylcholine), including synaptobrevin, SNAP-25, and
syntaxin. These proteins comprise the synaptic members of the SNARE complex
(soluble NSF (N-ethylmaleimide-sensitive fusionprotein) attachment protein) that
have a central role in membrane fusion events. The selective proteolysis of
these SNARE proteins inhibits neurotransmitter release from neurons. Botulism
occurs via a series of processes that cause muscular paralysis in human and
animals.
PMID: 21747146 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22855961 | 1. POLR3-Related Leukodystrophy.
Bernard G(1), Vanderver A(2).
In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW,
Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of
Washington, Seattle; 1993–2024.
2012 Aug 2 [updated 2017 May 11].
Author information:
(1)Departments of Neurology and Neurosurgery and Pediatrics, McGill University,
Department of Medical Genetics, McGill University Health Center, Child Health
and Human Development Program, Research Institute of the McGill University
Health Center, Montreal, Quebec, Canada
(2)Division of Neurology, Children's Research Institute, Children's Hospital of
Philadelphia, Philadelphia, Pennsylvania
CLINICAL CHARACTERISTICS: POLR3-related leukodystrophy, a hypomyelinating
leukodystrophy with specific features on brain MRI, is characterized by varying
combinations of four major clinical findings: Neurologic dysfunction, typically
predominated by motor dysfunction (progressive cerebellar dysfunction, and to a
lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and
cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia,
oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities
such as short stature (in ~50% of individuals) with or without growth hormone
deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as
delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia,
typically progressing over several years and becoming severe. POLR3-related
leukodystrophy and 4H leukodystrophy are the two recognized terms for five
previously described overlapping clinical phenotypes (initially described as
distinct entities before their molecular basis was known). These include:
Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome);
Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with
central hypomyelination (TACH); Leukodystrophy with oligodontia (LO);
Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum
(HCAHC). Age of onset is typically in early childhood but later-onset cases have
also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal
progeroid syndrome) was recently reported to have pathogenic variants in POLR3A
on exome sequencing. Confirmation of this as a very severe form of POLR3-related
leukodystrophy awaits replication in other individuals with a clinical diagnosis
of Wiedemann-Rautenstrauch syndrome.
DIAGNOSIS/TESTING: POLR3-related leukodystrophy is diagnosed by the combination
of classic clinical findings, typical brain MRI features, and the presence of
biallelic pathogenic variants in POLR3A, POLR3B, or POLR1C.
MANAGEMENT: Treatment of manifestations: Individualized care by a
multidisciplinary team including a pediatric neurologist, clinical geneticist,
physiotherapist, occupational therapist, speech and language pathologist,
neuropsychologist, rehabilitation physician, dentist, endocrinologist,
ophthalmologist, ear-nose-and-throat specialist, and primary care physician is
recommended. Special caution needs to be taken when managing dysphagia in this
disorder as it is known to vary widely, even in a single day. Swallowing
difficulties will progress over time and dystonia should be monitored and
treated to prevent complications and improve the quality of life.
GENETIC COUNSELING: POLR3-related leukodystrophy is inherited in an autosomal
recessive manner. At conception, each sib of an affected individual has a 25%
chance of being affected, a 50% chance of being an asymptomatic carrier, and a
25% chance of being unaffected and not a carrier. Carrier testing for at-risk
relatives and prenatal diagnosis for pregnancies at increased risk are possible
if both pathogenic variants in the family are known.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a
registered trademark of the University of Washington, Seattle. All rights
reserved.
PMID: 22855961 |
http://www.ncbi.nlm.nih.gov/pubmed/17428788 | 1. J Biol Chem. 2007 Jun 1;282(22):16391-400. doi: 10.1074/jbc.M700011200. Epub
2007 Apr 11.
Overlapping roles of the methylated DNA-binding protein MBD1 and polycomb group
proteins in transcriptional repression of HOXA genes and heterochromatin foci
formation.
Sakamoto Y(1), Watanabe S, Ichimura T, Kawasuji M, Koseki H, Baba H, Nakao M.
Author information:
(1)Department of Regeneration Medicine, Institute of Molecular Embryology and
Genetics, Graduate School of Medical Sciences, Kumamoto University, 2-2-1 Honjo,
Kumamoto 860-0811, Japan.
Methylated DNA binding domain (MBD) proteins and Polycomb group (PcG) proteins
maintain epigenetic silencing of transcriptional activity. We report that the
DNA methylation-mediated repressor MBD1 interacts with Ring1b and hPc2, the
major components of Polycomb repressive complex 1. The cysteine-rich CXXC
domains of MBD1 bound to Ring1b and the chromodomain of hPc2. Chromatin
immunoprecipitation analysis revealed that MBD1 and hPc2 were present in
silenced Homeobox A (HOXA) genes which could be reactivated by knockdown of
either MBD1 or hPc2, suggesting that MBD1 and hPc2 cooperate for transcriptional
repression of HOXA genes. In the nuclei of HeLa cells, MBD1 existed in close
association with these PcG proteins in some heterochromatin foci, whereas an
MBD1 mutant lacking the CXXC domains or an hPc2 mutant lacking the chromodomain
lost this colocalization in foci. Use of the DNA demethylating agent
5-azadeoxycytidine abolished the formation of MBD1 foci but not PcG foci.
Knockdown of MBD1 by small interfering RNAs did not affect the foci containing
hPc2 and Ring1b, whereas the MBD1 foci were not influenced by knockdown of hPc2.
These indicate that the heterochromatin foci showing MBD1 and hPc2
colocalization arise through the interaction of MBD1 and hPc2 and that the foci
of MBD1 are separable from those of the PcG proteins per se. Our present
findings suggest that MBD1 and PcG proteins have overlapping roles in epigenetic
gene silencing and heterochromatin foci formation through their interactions.
DOI: 10.1074/jbc.M700011200
PMID: 17428788 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21211724 | 1. Mol Cell. 2011 Jan 7;41(1):67-81. doi: 10.1016/j.molcel.2010.12.016.
Chromodomain-mediated oligomerization of HP1 suggests a nucleosome-bridging
mechanism for heterochromatin assembly.
Canzio D(1), Chang EY, Shankar S, Kuchenbecker KM, Simon MD, Madhani HD,
Narlikar GJ, Al-Sady B.
Author information:
(1)Department of Biochemistry and Biophysics, University of California, San
Francisco, San Francisco, CA 94158, USA.
HP1 proteins are central to the assembly and spread of heterochromatin
containing histone H3K9 methylation. The chromodomain (CD) of HP1 proteins
specifically recognizes the methyl mark on H3 peptides, but the same extent of
specificity is not observed within chromatin. The chromoshadow domain of HP1
proteins promotes homodimerization, but this alone cannot explain
heterochromatin spread. Using the S. pombe HP1 protein, Swi6, we show that
recognition of H3K9-methylated chromatin in vitro relies on an interface between
two CDs. This interaction causes Swi6 to tetramerize on a nucleosome, generating
two vacant CD sticky ends. On nucleosomal arrays, methyl mark recognition is
highly sensitive to internucleosomal distance, suggesting that the CD sticky
ends bridge nearby methylated nucleosomes. Strengthening the CD-CD interaction
enhances silencing and heterochromatin spread in vivo. Our findings suggest that
recognition of methylated nucleosomes and HP1 spread on chromatin are
structurally coupled and imply that methylation and nucleosome arrangement
synergistically regulate HP1 function.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2010.12.016
PMCID: PMC3752404
PMID: 21211724 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19399177 | 1. PLoS One. 2009;4(4):e5335. doi: 10.1371/journal.pone.0005335. Epub 2009 Apr
28.
The chromodomain of LIKE HETEROCHROMATIN PROTEIN 1 is essential for H3K27me3
binding and function during Arabidopsis development.
Exner V(1), Aichinger E, Shu H, Wildhaber T, Alfarano P, Caflisch A, Gruissem W,
Köhler C, Hennig L.
Author information:
(1)Department of Biology & Zurich-Basel Plant Science Center, ETH Zurich,
Zurich, Switzerland.
Polycomb group (PcG) proteins are essential to maintain gene expression patterns
during development. Transcriptional repression by PcG proteins involves
trimethylation of H3K27 (H3K27me3) by Polycomb Repressive Complex 2 (PRC2) in
animals and plants. PRC1 binds to H3K27me3 and is required for transcriptional
repression in animals, but in plants PRC1-like activities have remained elusive.
One candidate protein that could be involved in PRC1-like functions in plants is
LIKE HETEROCHROMATIN PROTEIN 1 (LHP1), because LHP1 associates with genes marked
by H3K27me3 in vivo and has a chromodomain that binds H3K27me3 in vitro. Here,
we show that disruption of the chromodomain of Arabidopsis thaliana LHP1
abolishes H3K27me3 recognition, releases gene silencing and causes similar
phenotypic alterations as transcriptional lhp1 null mutants. Therefore, binding
to H3K27me3 is essential for LHP1 protein function.
DOI: 10.1371/journal.pone.0005335
PMCID: PMC2670505
PMID: 19399177 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/22033296 | 1. J Mol Diagn. 2012 Jan;14(1):46-55. doi: 10.1016/j.jmoldx.2011.08.003. Epub
2011 Oct 25.
Complete screening of 50 patients with CHARGE syndrome for anomalies in the CHD7
gene using a denaturing high-performance liquid chromatography-based protocol:
new guidelines and a proposal for routine diagnosis.
Bilan F(1), Legendre M, Charraud V, Manière B, Couet D, Gilbert-Dussardier B,
Kitzis A.
Author information:
(1)Department of Genetics, Poitiers University Hospital, Poitiers, France.
Ocular coloboma, heart malformation, choanal atresia, retardation of growth
and/or development, genital hypoplasia, and ear anomalies associated with
deafness (CHARGE) syndrome is a rare, usually sporadic, autosomal dominant
disorder, caused by mutations within the CHD7 (chromodomain helicase DNA-binding
protein 7) gene, in nearly 70% of cases. Because human CHD7 is relatively large
(38 exons encoding a 300-kDa protein), genetic analysis requires cost-effective
and time-consuming techniques. Herein, we propose an alternative screening
method to quickly detect CHD7 mutations using mainly denaturing high-performance
liquid chromatography. The entire coding region with exon-intron boundaries was
amplified under the same experimental conditions. Each amplicon of the same CHD7
region was subjected to denaturing high-performance liquid chromatography
analysis, and resulting chromatograms were compared within small series of
patients. Because a CHD7 mutation differs generally from one patient to another,
corresponding chromatograms exhibited a unique pattern that is significantly
different from common polymorphisms. Only amplicons exhibiting a unique profile
were subjected to DNA sequencing analysis. Intragenic rearrangements were
investigated with only nine multiplex PCRs. In conclusion, using our protocol,
we can quickly detect the right containing mutation amplicon and we provide a
robust, rapid, and cheaper method to screen CHD7 microrearrangements or an
entire deletion.
Copyright © 2012 American Society for Investigative Pathology and the
Association for Molecular Pathology. Published by Elsevier Inc. All rights
reserved.
DOI: 10.1016/j.jmoldx.2011.08.003
PMID: 22033296 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12217960 | 1. Hum Mol Genet. 2002 Sep 15;11(19):2319-29. doi: 10.1093/hmg/11.19.2319.
Poly(ADP-ribose) polymerase 2 localizes to mammalian active centromeres and
interacts with PARP-1, Cenpa, Cenpb and Bub3, but not Cenpc.
Saxena A(1), Wong LH, Kalitsis P, Earle E, Shaffer LG, Choo KH.
Author information:
(1)The Murdoch Childrens Research Institute, Royal Children's Hospital,
Flemington Road, Parkville 3052, Australia.
Poly(ADP-ribose) polymerase 2 (PARP-2) is a newly discovered member of the PARP
family. We report the association of PARP-2 with mammalian centromeres in a
cell-cycle-dependent manner, accumulating at centromeres during prometaphase and
metaphase, disassociating during anaphase, and disappearing from the centromeres
by telophase. Analysis of a pseudodicentric chromosome and a human neocentromere
indicates that PARP-2 binding occurs only at active centromeres in a
sequence-independent manner. Centromere binding peaks at the outer centromere
region, and is significantly enhanced upon treatment with microtubule-inhibiting
drugs. Co-immunoprecipitation assay demonstrates interaction between PARP-2 and
its functional homolog PARP-1, constitutive centromere proteins Cenpa and Cenpb,
and spindle checkpoint protein Bub3, but not with a third constitutive
centromere protein Cenpc. These results, together with our previous
demonstration that PARP-1 displays an identical binding pattern with Cenpa,
Cenpb and Bub3, but not Cenpc, and that all three proteins undergo significant
poly(ADP-ribosyl)ation upon gamma-irradiation of cells, point to possible
diverse roles of PARP-2 and PARP-1 in modulating the structure and checkpoint
functions of the mammalian centromere, in particular during radiation-induced
DNA damage.
DOI: 10.1093/hmg/11.19.2319
PMID: 12217960 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11353082 | 1. Nucleic Acids Res. 2001 May 15;29(10):2127-34. doi: 10.1093/nar/29.10.2127.
Two Arabidopsis methylation-deficiency mutations confer only partial effects on
a methylated endogenous gene family.
Bartee L(1), Bender J.
Author information:
(1)Department of Biochemistry and Molecular Biology, Johns Hopkins University
School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA.
In Arabidopsis a SWI2/SNF2 chromatin remodeling factor-related protein DDM1 and
a cytosine methyltransferase MET1 are required for maintenance of genomic
cytosine methylation. Mutations in either gene cause global demethylation. In
this work we have assessed the effects of these mutations on the PAI tryptophan
biosynthetic gene family, which consists of four densely methylated genes
arranged as a tail-to-tail inverted repeat plus two unlinked singlet genes. The
methylation mutations caused only partial demethylation of the PAI loci: ddm1
had a strong effect on the singlet genes but a weaker effect on the inverted
repeat, whereas met1 had a stronger effect on the inverted repeat than on the
singlet genes. The double ddm1 met1 mutant also displayed partial demethylation
of the PAI genes, with a pattern similar to the ddm1 single mutant. To determine
the relationship between partial methylation and expression for the singlet PAI2
gene we constructed a novel reporter strain of Arabidopsis in which PAI2
silencing could be monitored by a blue fluorescent plant phenotype diagnostic of
tryptophan pathway defects. This reporter strain revealed that intermediate
levels of methylation correlate with intermediate suppression of the fluorescent
phenotype.
DOI: 10.1093/nar/29.10.2127
PMCID: PMC55449
PMID: 11353082 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21508988 | 1. Nat Rev Mol Cell Biol. 2011 May;12(5):320-32. doi: 10.1038/nrm3107.
Centromeres: unique chromatin structures that drive chromosome segregation.
Verdaasdonk JS(1), Bloom K.
Author information:
(1)Department of Biology, University of North Carolina at Chapel Hill, Chapel
Hill, North Carolina 27599, USA.
Fidelity during chromosome segregation is essential to prevent aneuploidy. The
proteins and chromatin at the centromere form a unique site for kinetochore
attachment and allow the cell to sense and correct errors during chromosome
segregation. Centromeric chromatin is characterized by distinct chromatin
organization, epigenetics, centromere-associated proteins and histone variants.
These include the histone H3 variant centromeric protein A (CENPA), the
composition and deposition of which have been widely investigated. Studies have
examined the structural and biophysical properties of the centromere and have
suggested that the centromere is not simply a 'landing pad' for kinetochore
formation, but has an essential role in mitosis by assembling and directing the
organization of the kinetochore.
DOI: 10.1038/nrm3107
PMCID: PMC3288958
PMID: 21508988 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests statement The authors
declare no competing financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/19778997 | 1. Reproduction. 2010 Jan;139(1):129-37. doi: 10.1530/REP-08-0435.
Dynamics of constitutive heterochromatin: two contrasted kinetics of genome
restructuring in early cloned bovine embryos.
Pichugin A(1), Le Bourhis D, Adenot P, Lehmann G, Audouard C, Renard JP, Vignon
X, Beaujean N.
Author information:
(1)INRA, UMR 1198 Biologie du développement et reproduction, F-78350 Jouy en
Josas, France.
Efficient reprograming of the donor cell genome in nuclear transfer (NT) embryos
is linked to the ability of the embryos to sustain full-term development. As the
nuclear architecture has recently emerged as a key factor in the regulation of
gene expression, we questioned whether early bovine embryos obtained from
transfer of cultured fibroblasts into enucleated oocytes would adopt an
embryo-like nuclear organization. We studied the dynamics of constitutive
heterochromatin in the stages prior to embryonic genome activation by
distribution analysis of heterochromatin protein CBX1 (HP1), centromeric
proteins CENPA and CENPB, and histone H3 three-methylated at lysine 9. Then we
applied descriptive, quantitative, and co-localization analyses. A dramatic
reorganization of heterochromatic blocks of somatic donor cells was first
observed in the late one-cell stage NT embryos. Then at two- and four-cell
stages, we found two types of NT embryos: one displaying noncondensed
heterochromatin patches similar to IVF embryos, whereas the second type
displayed condensed heterochromatin blocks, normally observed in IVF embryos
only after the eight-cell stage. These analyses discriminate for the first time
two contrasted types of nuclear organization in NT embryos, which may correspond
to different functional states of the nuclei. The relationship with the somatic
nucleus reprograming efficiency is discussed.
DOI: 10.1530/REP-08-0435
PMID: 19778997 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18411404 | 1. Genome Res. 2008 Jul;18(7):1064-72. doi: 10.1101/gr.075374.107. Epub 2008 Apr
14.
A high-resolution map of nucleosome positioning on a fission yeast centromere.
Song JS(1), Liu X, Liu XS, He X.
Author information:
(1)Department of Biostatistics and Computational Biology, Dana-Farber Cancer
Institute, Boston, Massachusetts 02115, USA.
A key element for defining the centromere identity is the incorporation of a
specific histone H3, CENPA, known as Cnp1p in Schizosaccharomyces pombe.
Previous studies have suggested that functional S. pombe centromeres lack
regularly positioned nucleosomes and may involve chromatin remodeling as a key
step of kinetochore assembly. We used tiling microarrays to show that
nucleosomes are, in fact, positioned in regular intervals in the core of
centromere 2, providing the first high-resolution map of regional centromere
chromatin. Nucleosome locations are not disrupted by mutations in kinetochore
protein genes cnp1, mis18, mis12, nuf2, mal2; overexpression of cnp1; or the
deletion of ams2, which encodes a GATA-like factor participating in CENPA
incorporation. Bioinformatics analysis of the centromere sequence indicates
certain enriched motifs in linker regions between nucleosomes and reveals a
sequence bias in nucleosome positioning. In addition, sequence analysis of
nucleosome-free regions identifies novel binding sites of Ams2p. We conclude
that centromeric nucleosome positions are stable and may be derived from the
underlying DNA sequence.
DOI: 10.1101/gr.075374.107
PMCID: PMC2493395
PMID: 18411404 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9680985 | 1. Plant J. 1998 Feb;13(3):317-29. doi: 10.1046/j.1365-313x.1998.00034.x.
Carrot DNA-methyltransferase is encoded by two classes of genes with differing
patterns of expression.
Bernacchia G(1), Primo A, Giorgetti L, Pitto L, Cella R.
Author information:
(1)Dipartimento di Genetica e Microbiologia, Università di Pavia, Italy.
In the present study, the isolation and characterization of two distinct cDNAs
that code for carrot DNA (cytosine-5)-methyltransferase (DNA-METase) are
reported. The screening of a cDNA library with a carrot genomic DNA fragment,
previously obtained by PCR using degenerate primers, has led to the isolation of
clones that belong to two distinct classes of genes (Met1 and Met2) which differ
in sequence and size. Met1-5 and Met2-21 derived amino acid sequences are more
than 85% identical for most of the polypeptide and completely diverge at the
N-terminus. The larger size of the Met2-21 cDNA is due to the presence of nearly
perfect fivefold repeat of a 171 bp sequence present only once in the Met1-5
cDNA. Northern and in situ hybridization analyses with young carrot plants and
somatic embryos indicate that both genes are maximally expressed in
proliferating cells (suspension cells, meristems and leaf primordia), but differ
quantitatively and spatially in their mode of expression. Polyclonal antibodies
were raised in rabbit using fusion proteins corresponding to the regulatory and
catalytic regions of the most highly expressed gene (Met1-5). In nuclear carrot
extracts, both antibodies were found to recognize a band of about 200 kDa along
with some additional bands of lower size. These results provide the first direct
demonstration that DNA-METases of a higher eukaryote are encoded by a gene
family.
DOI: 10.1046/j.1365-313x.1998.00034.x
PMID: 9680985 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8152926 | 1. RETRACTED ARTICLE
Nucleic Acids Res. 1994 Mar 25;22(6):953-8. doi: 10.1093/nar/22.6.953.
Are there two DNA methyltransferase gene families in plant cells? A new
potential methyltransferase gene isolated from an Arabidopsis thaliana genomic
library.
Scheidt G(1), Weber H, Graessmann M, Graessmann A.
Author information:
(1)Institut für Molekularbiologie und Biochemie, Freien Universität Berlin,
Germany.
Retraction in
Nucleic Acids Res. 1994 Nov 25;22(23):5138.
Using the 1kb 3' terminal DNA fragment of the mouse methyltransferase cDNA as a
probe and low stringent hybridisation conditions, a new potential
methyltransferase (MTase) gene family was isolated from an Arabidopsis thaliana
genomic DNA library. One clone (MTase-11), which gave the strongest signal at
the Northern blot, was entirely sequenced (11483 bp) and further characterised.
Under consideration of the likely open reading frames and our preliminary cDNA
experiments we propose that the clone 11 gene encodes for an approximately 90 kD
protein. As deduced form the DNA sequence this protein contains all conserved
sequence motifs specific for the 5m cytosine MTases. MTase-11 gene expression
was demonstrable in callus and during germination but not in one month old
plants or in leaves.
DOI: 10.1093/nar/22.6.953
PMCID: PMC320484
PMID: 8152926 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22179824 | 1. Oncogene. 2012 Sep 13;31(37):4164-70. doi: 10.1038/onc.2011.590. Epub 2011 Dec
19.
Recurrent deletion of CHD1 in prostate cancer with relevance to cell
invasiveness.
Huang S(1), Gulzar ZG, Salari K, Lapointe J, Brooks JD, Pollack JR.
Author information:
(1)Department of Pathology, Stanford University School of Medicine, Stanford, CA
94305-5176, USA.
Though prostate cancer is often indolent, it is nonetheless a leading cause of
cancer death. Defining the underlying molecular genetic alterations may lead to
new strategies for prevention or treatment. Towards this goal, we performed
array-based comparative genomic hybridization (CGH) on 86 primary prostate
tumors. Among the most frequent alterations not associated with a known cancer
gene, we identified focal deletions within 5q21 in 15 out of 86 (17%) cases. By
high-resolution tiling array CGH, the smallest common deletion targeted just one
gene, the chromatin remodeler chromodomain helicase DNA-binding protein 1
(CHD1). Expression of CHD1 was significantly reduced in tumors with deletion
(P=0.03), and compared with normal prostate (P=0.04). Exon sequencing analysis
also uncovered nonsynonymous mutations in 1 out of 7 (14%) cell lines (LAPC4)
and in 1 out of 24 (4%) prostate tumors surveyed. RNA interference-mediated
knockdown of CHD1 in two nontumorigenic prostate epithelial cell lines, OPCN2
and RWPE-1, did not alter cell growth, but promoted cell invasiveness, and in
OPCN2-enhanced cell clonogenicity. Taken together, our findings suggest that
CHD1 deletion may underlie cell invasiveness in a subset of prostate cancers,
and indicate a possible novel role of altered chromatin remodeling in prostate
tumorigenesis.
DOI: 10.1038/onc.2011.590
PMCID: PMC5512870
PMID: 22179824 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest The authors declare no
conflict of interest |
http://www.ncbi.nlm.nih.gov/pubmed/23071455 | 1. PLoS Genet. 2012;8(10):e1003006. doi: 10.1371/journal.pgen.1003006. Epub 2012
Oct 11.
New partners in regulation of gene expression: the enhancer of Trithorax and
Polycomb Corto interacts with methylated ribosomal protein l12 via its
chromodomain.
Coléno-Costes A(1), Jang SM, de Vanssay A, Rougeot J, Bouceba T, Randsholt NB,
Gibert JM, Le Crom S, Mouchel-Vielh E, Bloyer S, Peronnet F.
Author information:
(1)Université Pierre et Marie Curie-Paris 6, UMR7622, Laboratoire de Biologie du
Développement, Equipe Chromatine et Développement, Paris, France.
Chromodomains are found in many regulators of chromatin structure, and most of
them recognize methylated lysines on histones. Here, we investigate the role of
the Drosophila melanogaster protein Corto's chromodomain. The Enhancer of
Trithorax and Polycomb Corto is involved in both silencing and activation of
gene expression. Over-expression of the Corto chromodomain (CortoCD) in
transgenic flies shows that it is a chromatin-targeting module, critical for
Corto function. Unexpectedly, mass spectrometry analysis reveals that
polypeptides pulled down by CortoCD from nuclear extracts correspond to
ribosomal proteins. Furthermore, real-time interaction analyses demonstrate that
CortoCD binds with high affinity RPL12 tri-methylated on lysine 3. Corto and
RPL12 co-localize with active epigenetic marks on polytene chromosomes,
suggesting that both are involved in fine-tuning transcription of genes in open
chromatin. RNA-seq based transcriptomes of wing imaginal discs over-expressing
either CortoCD or RPL12 reveal that both factors deregulate large sets of common
genes, which are enriched in heat-response and ribosomal protein genes,
suggesting that they could be implicated in dynamic coordination of ribosome
biogenesis. Chromatin immunoprecipitation experiments show that Corto and RPL12
bind hsp70 and are similarly recruited on gene body after heat shock. Hence,
Corto and RPL12 could be involved together in regulation of gene transcription.
We discuss whether pseudo-ribosomal complexes composed of various ribosomal
proteins might participate in regulation of gene expression in connection with
chromatin regulators.
DOI: 10.1371/journal.pgen.1003006
PMCID: PMC3469418
PMID: 23071455 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/21636313 | 1. Oral Oncol. 2011 Jul;47(7):601-8. doi: 10.1016/j.oraloncology.2011.05.003.
Epub 2011 Jun 1.
The involvement of CHD5 hypermethylation in laryngeal squamous cell carcinoma.
Wang J(1), Chen H, Fu S, Xu ZM, Sun KL, Fu WN.
Author information:
(1)Department of Medical Genetics, China Medical University, 92 Beier Road,
Heping District, Shenyang 110001, PR China.
Chromodomain helicase DNA-binding protein 5 (CHD5) has been found to be a
candidate tumor suppressor gene (TSG) in malignant neural tumors. In mice
heterozygous for chd5 deficiency, the first tumor observed was pathological
squamous cell carcinoma. More than 95% of primary laryngeal cancer is squamous
cell carcinoma. Thus, we explored the expression of CHD5 in 65 patients with
laryngeal squamous cell carcinoma (LSCC) using real-time PCR,
immunohistochemistry and Western blotting. DNA methylation was detected using
bisulfate-specific sequencing. The potential function of CHD5 was determined
using MTT, apoptosis and transwell migration assays in CHD5-transfected Hep-2
cells. Our results revealed that the mRNA and protein expression levels of CHD5
in LSCC tissues were significantly lower than those in clear surgical margin
tissues (p<0.05), and there is a significant correlation between the mRNA and
protein expression levels of CHD5 (p<0.01). In addition, there were significant
differences in CHD5 mRNA and protein levels with respect to the patient's
clinical stage (p<0.05). Aberrant methylation of the CHD5 promoter was
frequently found in the Hep-2 cell line and LSCC tumor tissues, especially tumor
tissues from advanced TNM (p<0.05) or older patients (p<0.05). Finally, ectopic
expression of CHD5 in laryngeal cancer cells led to significant inhibition of
growth and invasiveness. Our data suggest that CHD5 is a tumor suppressor gene
that is epigenetically downregulated in LSCC.
Copyright © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.oraloncology.2011.05.003
PMID: 21636313 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24213134 | 1. Cancers (Basel). 2011 Dec 6;3(4):4212-27. doi: 10.3390/cancers3044212.
Immunohistochemical Assessment of Expression of Centromere Protein-A (CENPA) in
Human Invasive Breast Cancer.
Rajput AB(1), Hu N, Varma S, Chen CH, Ding K, Park PC, Chapman JA, Sengupta SK,
Madarnas Y, Elliott BE, Feilotter HE.
Author information:
(1)Department of Pathology and Molecular Medicine, Queen's University, Kingston,
ON K7L 3N6, Canada. feilotth@kgh.kari.net.
Abnormal cell division leading to the gain or loss of entire chromosomes and
consequent genetic instability is a hallmark of cancer. Centromere protein -A
(CENPA) is a centromere-specific histone-H3-like variant gene involved in
regulating chromosome segregation during cell division. CENPA is one of the
genes included in some of the commercially available RNA based prognostic assays
for breast cancer (BCa)-the 70 gene signature MammaPrint® and the five gene
Molecular Grade Index (MGISM). Our aim was to assess the immunohistochemical
(IHC) expression of CENPA in normal and malignant breast tissue. Clinically
annotated triplicate core tissue microarrays of 63 invasive BCa and 20 normal
breast samples were stained with a monoclonal antibody against CENPA and scored
for percentage of visibly stained nuclei. Survival analyses with Kaplan-Meier
(KM) estimate and Cox proportional hazards regression models were applied to
assess the associations between CENPA expression and disease free survival
(DFS). Average percentage of nuclei visibly stained with CENPA antibody was
significantly higher (p = 0.02) in BCa than normal tissue. The 3-year DFS in
tumors over-expressing CENPA (>50% stained nuclei) was 79% compared to 85% in
low expression tumors ( 60.07; p = 0.06) within our small cohort. To the best of
our knowledge, this is the first published report evaluating the implications of
increased IHC expression of CENPA in paraffin embedded breast tissue samples.
Our finding that increased CENPA expression may be associated with shorter DFS
in BCa supports its exploration as a potential prognostic biomarker.
DOI: 10.3390/cancers3044212
PMCID: PMC3763419
PMID: 24213134 |
http://www.ncbi.nlm.nih.gov/pubmed/22022377 | 1. PLoS One. 2011;6(10):e25104. doi: 10.1371/journal.pone.0025104. Epub 2011 Oct
12.
Structural basis for specific binding of human MPP8 chromodomain to histone H3
methylated at lysine 9.
Li J(1), Li Z, Ruan J, Xu C, Tong Y, Pan PW, Tempel W, Crombet L, Min J, Zang J.
Author information:
(1)Key Laboratory of Structural Biology, Chinese Academy of Sciences, and School
of Life Sciences, University of Science and Technology of China, Hefei, Anhui,
People's Republic of China.
BACKGROUND: M-phase phosphoprotein 8 (MPP8) was initially identified to be a
component of the RanBPM-containing large protein complex, and has recently been
shown to bind to methylated H3K9 both in vivo and in vitro. MPP8 binding to
methylated H3K9 is suggested to recruit the H3K9 methyltransferases GLP and
ESET, and DNA methyltransferase 3A to the promoter of the E-cadherin gene,
mediating the E-cadherin gene silencing and promote tumor cell motility and
invasion. MPP8 contains a chromodomain in its N-terminus, which is used to bind
the methylated H3K9.
METHODOLOGY/PRINCIPAL FINDINGS: Here, we reported the crystal structures of
human MPP8 chromodomain alone and in complex with the trimethylated histone H3K9
peptide (residue 1-15). The complex structure unveils that the human MPP8
chromodomain binds methylated H3K9 through a conserved recognition mechanism,
which was also observed in Drosophila HP1, a chromodomain containing protein
that binds to methylated H3K9 as well. The structure also reveals that the human
MPP8 chromodomain forms homodimer, which is mediated via an unexpected domain
swapping interaction through two β strands from the two protomer subunits.
CONCLUSIONS/SIGNIFICANCE: Our findings reveal the molecular mechanism of
selective binding of human MPP8 chromodomain to methylated histone H3K9. The
observation of human MPP8 chromodomain in both solution and crystal lattice may
provide clues to study MPP8-mediated gene regulation furthermore.
DOI: 10.1371/journal.pone.0025104
PMCID: PMC3192050
PMID: 22022377 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/20389031 | 1. Cytogenet Genome Res. 2010;128(1-3):152-61. doi: 10.1159/000290557. Epub 2010
Apr 9.
Possible heterochromatin horizontal spread through non-homologous chromosome
associations in pachytene chromocenters of Ctenomys Rodents.
Novello A(1), Villar S, Urioste J.
Author information:
(1)Sección Genética Evolutiva, Instituto de Biología, Montevideo, Uruguay.
anovello@fcien.edu.uy
Comment in
Cytogenet Genome Res. 2011;134(2):163-4. doi: 10.1159/000324700.
Heterochromatin patterns were analyzed in the genus Ctenomys from Uruguay which
exhibits high karyotype variability. Different amounts and localizations of
heterochromatin were observed in species and populations analyzed. While species
as C. rionegrensis presented heterochromatic arms in all the chromosomes of the
karyotype, other species like C. torquatus showed only few chromosomes with
pericentric heterochromatin. At the pachytene stage, bivalents merge in densely
stained chromocenters. We detected in these chromocenters the typical highly
repeated DNA of this genus after in situ hybridization, the M31 chromodomain
through immunofluorescence as well as dense Giemsa staining after C-banding. In
species that present low amounts of heterochromatin, only 1 or 2 chromocenters
were observed in which bivalents merge as observed in C. rionegrensis. After
BRCA1 immunodetection we observed in early pachytene cells positive spots
located over heterochromatic chromocenters that strongly suggest heterochromatic
DNA repair. Mechanical stress mainly due to increasing chromatin compactness
before metaphase I might be a mechanism to spread heterochromatin between
different chromosomes within a karyotype.
Copyright 2010 S. Karger AG, Basel.
DOI: 10.1159/000290557
PMID: 20389031 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21158681 | 1. Genet Test Mol Biomarkers. 2010 Dec;14(6):881-91. doi: 10.1089/gtmb.2010.0101.
Mutations in the CHD7 gene: the experience of a commercial laboratory.
Bartels CF(1), Scacheri C, White L, Scacheri PC, Bale S.
Author information:
(1)Department of Genetics, Case Western Reserve University, Cleveland, Ohio
44016, USA.
CHARGE syndrome is an autosomal dominant multisystem disorder caused by mutation
in the CHD7 gene, encoding chromodomain helicase DNA-binding protein 7.
Molecular diagnostic testing for CHD7 mutation has been available in a clinical
setting since 2005. We report here the results from the first 642 unrelated
proband samples submitted for testing. Thirty-two percent (n = 203) of patient
samples had a heterozygous pathogenic variant identified. The lower mutation
rate than that published for well-characterized clinical samples is likely due
to referral bias, as samples submitted for clinical testing may be for
"rule-out" diagnoses, rather than solely to confirm clinical suspicion. We
identified 159 unique pathogenic mutations, and of these, 134 mutations were
each seen in a single individual and 25 mutations were found in two to five
individuals (n =69). Of the 203 mutations, only 9 were missense, with 107
nonsense, 69 frameshift, and 15 splice-site mutations likely leading to
haploinsufficiency at the cellular level. An additional 72 variations identified
in the 642 tested samples (11%) were considered to have unknown clinical
significance. Copy number changes (deletion/duplication of the entire gene or
one/several exons) were found to account for a very small number of cases (n =
3). This cohort represents the largest CHARGE syndrome sample size to date and
is intended to serve as a resource for clinicians, genetic counselors,
researchers, and other diagnostic laboratories.
DOI: 10.1089/gtmb.2010.0101
PMCID: PMC3001831
PMID: 21158681 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20119530 | 1. Curr Genomics. 2009 Aug;10(5):326-35. doi: 10.2174/138920209788920985.
CENPA a genomic marker for centromere activity and human diseases.
Valdivia MM(1), Hamdouch K, Ortiz M, Astola A.
Author information:
(1)Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias,
Universidad de Cádiz, 11510 Puerto Real, Cádiz, Spain. manuel.valdivia@uca.es
Inheritance of genetic material requires that chromosomes segregate faithfully
during cell division. Failure in this process can drive to aneuploidy
phenomenon. Kinetochores are unique centromere macromolecular protein structures
that attach chromosomes to the spindle for a proper movement and segregation. A
unique type of nucleosomes of centromeric chromatin provides the base for
kinetochore formation. A specific histone H3 variant, CENPA, replaces
conventional histone H3 and together with centromere-specific-DNA-binding
factors directs the assembly of active kinetochores. Recent studies on CENPA
nucleosomal structure, epigenetic inheritance of centromeric chromatin and
transcription of pericentric heterochromatin provide new clues to our
understanding of centromere structure and function. This review highlights the
role and dynamics of CENPA assembly into centromeres and the potential
contribution of this kinetochore protein to autoimmune and cancer diseases in
humans.
DOI: 10.2174/138920209788920985
PMCID: PMC2729997
PMID: 20119530 |
http://www.ncbi.nlm.nih.gov/pubmed/23285239 | 1. PLoS One. 2012;7(12):e52977. doi: 10.1371/journal.pone.0052977. Epub 2012 Dec
28.
Crystal structure of the human SUV39H1 chromodomain and its recognition of
histone H3K9me2/3.
Wang T(1), Xu C, Liu Y, Fan K, Li Z, Sun X, Ouyang H, Zhang X, Zhang J, Li Y,
Mackenzie F, Min J, Tu X.
Author information:
(1)Hefei National Laboratory for Physical Sciences at Microscale, School of Life
Science, University of Science and Technology of China, Hefei, Anhui, People's
Republic of China.
SUV39H1, the first identified histone lysine methyltransferase in human, is
involved in chromatin modification and gene regulation. SUV39H1 contains a
chromodomain in its N-terminus, which potentially plays a role in methyl-lysine
recognition and SUV39H1 targeting. In this study, the structure of the
chromodomain of human SUV39H1 was determined by X-ray crystallography. The
SUV39H1 chromodomain displays a generally conserved structure fold compared with
other solved chromodomains. However, different from other chromodomains, the
SUV39H1 chromodomain possesses a much longer helix at its C-terminus.
Furthermore, the SUV39H1 chromodomain was shown to recognize histone H3K9me2/3
specifically.
DOI: 10.1371/journal.pone.0052977
PMCID: PMC3532415
PMID: 23285239 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors declare that
they received funding from commercial sources - GlaxoSmithKline and Merck & Co.,
Inc. However, this does not alter the authors’ adherence to all the PLOS ONE
policies on sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/17542647 | 1. PLoS Genet. 2007 Jun;3(6):e86. doi: 10.1371/journal.pgen.0030086. Epub 2007
Apr 17.
Arabidopsis TFL2/LHP1 specifically associates with genes marked by
trimethylation of histone H3 lysine 27.
Turck F(1), Roudier F, Farrona S, Martin-Magniette ML, Guillaume E, Buisine N,
Gagnot S, Martienssen RA, Coupland G, Colot V.
Author information:
(1)Abteilung Entwicklungsbiologie der Pflanzen, Max Planck Institut für
Züchtungsforschung, Cologne, Germany.
TERMINAL FLOWER 2/LIKE HETEROCHROMATIN PROTEIN 1 (TFL2/LHP1) is the only
Arabidopsis protein with overall sequence similarity to the HETEROCHROMATIN
PROTEIN 1 (HP1) family of metazoans and S. pombe. TFL2/LHP1 represses
transcription of numerous genes, including the flowering-time genes FLOWERING
LOCUS T (FT) and FLOWERING LOCUS C (FLC), as well as the floral organ identity
genes AGAMOUS (AG) and APETALA 3 (AP3). These genes are also regulated by
proteins of the Polycomb repressive complex 2 (PRC2), and it has been proposed
that TFL2/LHP1 represents a potential stabilizing factor of PRC2 activity. Here
we show by chromatin immunoprecipitation and hybridization to an Arabidopsis
Chromosome 4 tiling array (ChIP-chip) that TFL2/LHP1 associates with hundreds of
small domains, almost all of which correspond to genes located within
euchromatin. We investigated the chromatin marks to which TFL2/LHP1 binds and
show that, in vitro, TFL2/LHP1 binds to histone H3 di- or tri-methylated at
lysine 9 (H3K9me2 or H3K9me3), the marks recognized by HP1, and to histone H3
trimethylated at lysine 27 (H3K27me3), the mark deposited by PRC2. However, in
vivo TFL2/LHP1 association with chromatin occurs almost exclusively and
co-extensively with domains marked by H3K27me3, but not H3K9me2 or -3. Moreover,
the distribution of H3K27me3 is unaffected in lhp1 mutant plants, indicating
that unlike PRC2 components, TFL2/LHP1 is not involved in the deposition of this
mark. Rather, our data suggest that TFL2/LHP1 recognizes specifically H3K27me3
in vivo as part of a mechanism that represses the expression of many genes
targeted by PRC2.
DOI: 10.1371/journal.pgen.0030086
PMCID: PMC1885283
PMID: 17542647 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests. The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/21836164 | 1. Mol Cell Proteomics. 2011 Nov;10(11):M110.005371. doi:
10.1074/mcp.M110.005371. Epub 2011 Aug 11.
Chromatin affinity purification and quantitative mass spectrometry defining the
interactome of histone modification patterns.
Nikolov M(1), Stützer A, Mosch K, Krasauskas A, Soeroes S, Stark H, Urlaub H,
Fischle W.
Author information:
(1)Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical
Chemistry, 37077 Göttingen, Germany.
DNA and histone modifications direct the functional state of chromatin and
thereby the readout of the genome. Candidate approaches and histone peptide
affinity purification experiments have identified several proteins that bind to
chromatin marks. However, the complement of factors that is recruited by
individual and combinations of DNA and histone modifications has not yet been
defined. Here, we present a strategy based on recombinant, uniformly modified
chromatin templates used in affinity purification experiments in conjunction
with SILAC-based quantitative mass spectrometry for this purpose. On the
prototypic H3K4me3 and H3K9me3 histone modification marks we compare our method
with a histone N-terminal peptide affinity purification approach. Our analysis
shows that only some factors associate with both, chromatin and peptide matrices
but that a surprisingly large number of proteins differ in their association
with these templates. Global analysis of the proteins identified implies
specific domains mediating recruitment to the chromatin marks. Our
proof-of-principle studies show that chromatin templates with defined
modification patterns can be used to decipher how the histone code is read and
translated.
DOI: 10.1074/mcp.M110.005371
PMCID: PMC3226395
PMID: 21836164 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11956312 | 1. J Cell Sci. 2002 May 1;115(Pt 9):1803-13. doi: 10.1242/jcs.115.9.1803.
Loss of heterochromatin protein 1 (HP1) chromodomain function in mammalian cells
by intracellular antibodies causes cell death.
Filesi I(1), Cardinale A, van der Sar S, Cowell IG, Singh PB, Biocca S.
Author information:
(1)Department of Neuroscience, University of Roma Tor Vergata, Via Montpellier
1, 00133 Rome, Italy.
The chromodomain (CD) is a highly conserved motif present in a variety of animal
and plant proteins, and its probable role is to assemble a variety of
macromolecular complexes in chromatin. The importance of the CD to the survival
of mammalian cells has been tested. Accordingly, we have ablated CD function
using two single-chain intracellular Fv (scFv) fragments directed against
non-overlapping epitopes within the HP1 CD motif. The scFv fragments can
recognize both CD motifs of HP1 and Polycomb (Pc) in vitro and, when expressed
intracellularly, interact with and dislodge the HP1 protein(s) from their
heterochromatin localization in vivo. Mouse and human fibroblasts expressing
anti-chromodomain scFv fragments show a cell-lethal phenotype and an apoptotic
morphology becomes apparent soon after transfection. The mechanism of cell death
appears to be p53 independent, and the cells are only partly rescued by
incubation with the wide spectrum caspase inhibitor Z-VAD fmk. We conclude that
expression of anti-chromodomain intracellular antibodies is sufficient to
trigger a p53-independent apoptotic pathway that is only partly dependent on the
known Z-VAD-inhibitable caspases, suggesting that CD function is essential for
cell survival.
DOI: 10.1242/jcs.115.9.1803
PMID: 11956312 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22145013 | 1. Curr Chem Genomics. 2011;5:51-61. doi: 10.2174/1875397301005010051. Epub 2011
Aug 22.
Drug discovery toward antagonists of methyl-lysine binding proteins.
Herold JM(1), Ingerman LA, Gao C, Frye SV.
Author information:
(1)Center for Integrated Chemical Biology and Drug Discovery, UNC Eshelman
School of Pharmacy, Division of Medicinal Chemistry and Natural Products,
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,
USA.
The recognition of methyl-lysine and -arginine residues on both histone and
other proteins by specific "reader" elements is important for chromatin
regulation, gene expression, and control of cell-cycle progression. Recently the
crucial role of these reader proteins in cancer development and
dedifferentiation has emerged, owing to the increased interest among the
scientific community. The methyl-lysine and -arginine readers are a large and
very diverse set of effector proteins and targeting them with small molecule
probes in drug discovery will inevitably require a detailed understanding of
their structural biology and mechanism of binding. In the following review, the
critical elements of methyl-lysine and -arginine recognition will be summarized
with respect to each protein family and initial results in assay development,
probe design, and drug discovery will be highlighted.
DOI: 10.2174/1875397301005010051
PMCID: PMC3229088
PMID: 22145013 |
http://www.ncbi.nlm.nih.gov/pubmed/21830056 | 1. Chromosoma. 2011 Dec;120(6):609-19. doi: 10.1007/s00412-011-0335-8. Epub 2011
Aug 10.
Pairing of lacO tandem repeats in Arabidopsis thaliana nuclei requires the
presence of hypermethylated, large arrays at two chromosomal positions, but does
not depend on H3-lysine-9-dimethylation.
Jovtchev G(1), Borisova BE, Kuhlmann M, Fuchs J, Watanabe K, Schubert I, Mette
MF.
Author information:
(1)Leibniz Institute of Plant Genetics and Crop Plant Research (IPK)
Gatersleben, Germany.
Fluorescent chromatin tagging by the lacO operator/lac repressor system in
Arabidopsis thaliana is useful to trace distinct chromatin domains in living
cells. Nevertheless, the tandem repeats of the tagging system may alter the
spatial organisation of chromatin within nuclei by increasing homologous pairing
as well as association with heterochromatin. Efficient homologous pairing occurs
if lacO repeat arrays of ∼10 kb are present at two loci, either on the same
chromosome or on different chromosomes. DNA hypomethylation of lacO repeats
results in reduced homologous pairing. Because, in plants, DNA methylation can
serve as a signal for H3-lysine9-dimethylation (H3K9me2), and subsequently for
non-CG-context DNA methylation, SET-domain histone methyltransferase and
chromodomain dna methyltransferase 3 (cmt3) mutations were introgressed. In
suvh4 suvh5 suvh6 and cmt3 mutants, H3K9me2 associated with lacO repeats is
diminished, but homologous pairing persists. Thus, neither H3K9me2 nor
CMT3-mediated non-CG methylation are required at wild-type level for homologous
pairing of lacO repeat loci.
DOI: 10.1007/s00412-011-0335-8
PMID: 21830056 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22009739 | 1. J Biol Chem. 2011 Dec 9;286(49):42414-42425. doi: 10.1074/jbc.M111.271064.
Epub 2011 Oct 17.
Corepressor protein CDYL functions as a molecular bridge between polycomb
repressor complex 2 and repressive chromatin mark trimethylated histone lysine
27.
Zhang Y(1), Yang X(1), Gui B(1), Xie G(1), Zhang D(1), Shang Y(2), Liang J(3).
Author information:
(1)Key Laboratory of Carcinogenesis and Translational Research (Ministry of
Education), Department of Biochemistry and Molecular Biology, Peking University
Health Science Center, Beijing 100191, China.
(2)Key Laboratory of Carcinogenesis and Translational Research (Ministry of
Education), Department of Biochemistry and Molecular Biology, Peking University
Health Science Center, Beijing 100191, China; Tianjin Key Laboratory of Medical
Epigenetics, Tianjin Medical University, Tianjin 300070, China.
(3)Key Laboratory of Carcinogenesis and Translational Research (Ministry of
Education), Department of Biochemistry and Molecular Biology, Peking University
Health Science Center, Beijing 100191, China. Electronic address:
liang_jing@bjmu.edu.cn.
Polycomb group proteins play essential roles in transcriptional regulation of
multiple gene families involved in various pathophysiological processes. It is
believed that Polycomb Repressive Complex 2 (PRC2) is targeted to chromatin by
the EED subunit to methylate histone H3 lysine 27 (H3K27), leading to a
repressive chromatin state that inhibits gene expression. Here we report that
the chromodomain-containing protein CDYL specifically recognizes di- and
tri-methylated H3K27 (H3K27me2 and H3K27me3) and directly interacts with EZH2,
the catalytic subunit of PRC2. We show that CDYL dramatically enhances the
methyltransferase activity of PRC2 toward oligonucleosome substrates in vitro.
Genome-wide analysis of CDYL targets by ChIP sequencing revealed that CDYL and
PRC2 share a number of genomic targets. CDYL is required for chromatin targeting
and maximal enzymatic activity of PRC2 at their common target sites. Our
experiments indicate that CDYL functions as a molecular bridge between PRC2 and
the repressive chromatin mark H3K27me3, forming a positive feedback loop to
facilitate the establishment and propagation of H3K27me3 modifications along the
chromatin.
DOI: 10.1074/jbc.M111.271064
PMCID: PMC3234934
PMID: 22009739 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23320494 | 1. J Proteome Res. 2013 Mar 1;12(3):1467-77. doi: 10.1021/pr3011205. Epub 2013
Feb 4.
Recognition of methylated peptides by Drosophila melanogaster polycomb
chromodomain.
Stein RS(1), Li N, He W, Komives E, Wang W.
Author information:
(1)Department of Chemistry and Biochemistry, University of California, San
Diego, 9500 Gilman Drive, La Jolla, California 92093-0359, United States.
Lysine methylation is one of the important post-translational modifications
(PTMs) that regulate protein functions. Up to now, proteomic identification of
this PTM remains a challenge due to the lack of effective enrichment methods in
mass spectrometry experiments. To address this challenge, we present here a
systematic approach to predicting peptides in which lysine residues may be
methylated to mediate protein-protein interactions. We used the chromodomain of
the polycomb protein in Drosophila melanogaster as a model system to illustrate
the success of this approach. We started with molecular dynamics simulations and
free energy analyses on the histone peptides complexed with the polycomb
chromodomain to understand how the binding specificity is achieved. We next
conducted virtual mutagenesis to quantify each domain and peptide residue's
contribution to the domain-peptide recognition, based on which scoring scheme
was developed to evaluate the possibility of any lysine-containing peptides to
be methylated and recognized by the chromodomain. A peptide microarray
experiment on a panel of conserved histone peptides showed a satisfactory
prediction accuracy of the scoring scheme. Next, we implemented a bioinformatics
pipeline that integrates multiple lines of evidence including conservation,
subcellular localization, and mass spectrometry data to scan the fly proteome
for a systematic identification of possible methyllysine-containing peptides.
These putative chromodomain-binding peptides suggest unknown functions of the
important regulator protein polycomb and provide a list of candidate methylation
events for follow-up investigations.
DOI: 10.1021/pr3011205
PMCID: PMC4258113
PMID: 23320494 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21860208 | 1. Gynecol Obstet Invest. 2011;72(3):203-7. doi: 10.1159/000323883. Epub 2011 Aug
23.
CHD5 Downregulation Associated with Poor Prognosis in Epithelial Ovarian Cancer.
Wong RR(1), Chan LK, Tsang TP, Lee CW, Cheung TH, Yim SF, Siu NS, Lee SN, Yu MY,
Chim SS, Wong YF, Chung TK.
Author information:
(1)Departments of Obstetrics and Gynaecology, The Chinese University of Hong
Kong, Prince of Wales Hospital, Hong Kong, SAR, China.
BACKGROUND: The CHD5 gene located on 1p36 encodes a protein-chromodomain
helicase DNA-binding protein 5. CHD5 has been shown to be a tumor suppressor
gene candidate. This study investigated the involvement of CHD5 in ovarian
cancer and its clinicopathological significance.
METHODS: CHD5 expression in ovarian cancer and its counterpart were determined
by quantitative RT-PCR. The correlation of CHD5 expression to
clinicopathological features of the tumor was analyzed.
RESULTS: CHD5 expression was downregulated by at least twofold in 32 of 72 (41%)
invasive epithelial ovarian carcinomas when compared to 12 controls in Hong Kong
Chinese women. CHD5 downregulation was correlated to clinical status (p < 0.05),
but not to patient age, tumor type and grade, recurrence and clinical stage (p >
0.05). Survival analysis showed that patients with CHD5 downregulation in their
tumors were associated with shorter disease-free and total survival times
compared to those without CHD5 downregulation (p < 0.05). Cox
proportional-hazards regression analysis indicated that downregulation of CHD5
is an independent adverse prognostic factor in ovarian cancer.
CONCLUSION: This study shows that CHD5 is downregulated in a certain number of
ovarian cancers and appears to be an adverse predictor candidate of ovarian
cancer disease-free and total survival.
Copyright © 2011 S. Karger AG, Basel.
DOI: 10.1159/000323883
PMID: 21860208 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23285124 | 1. PLoS One. 2012;7(12):e52640. doi: 10.1371/journal.pone.0052640. Epub 2012 Dec
21.
Identification and characterization of FAM124B as a novel component of a CHD7
and CHD8 containing complex.
Batsukh T(1), Schulz Y, Wolf S, Rabe TI, Oellerich T, Urlaub H, Schaefer IM,
Pauli S.
Author information:
(1)Institute of Human Genetics, University Medical Center, Göttingen, Germany.
BACKGROUND: Mutations in the chromodomain helicase DNA binding protein 7 gene
(CHD7) lead to CHARGE syndrome, an autosomal dominant multiple malformation
disorder. Proteins involved in chromatin remodeling typically act in
multiprotein complexes. We previously demonstrated that a part of human CHD7
interacts with a part of human CHD8, another chromodomain helicase DNA binding
protein presumably being involved in the pathogenesis of neurodevelopmental
(NDD) and autism spectrum disorders (ASD). Because identification of novel CHD7
and CHD8 interacting partners will provide further insights into the
pathogenesis of CHARGE syndrome and ASD/NDD, we searched for additional
associated polypeptides using the method of stable isotope labeling by amino
acids in cell culture (SILAC) in combination with mass spectrometry.
PRINCIPLE FINDINGS: The hitherto uncharacterized FAM124B (Family with sequence
similarity 124B) was identified as a potential interaction partner of both CHD7
and CHD8. We confirmed the result by co-immunoprecipitation studies and showed a
direct binding to the CHD8 part by direct yeast two hybrid experiments.
Furthermore, we characterized FAM124B as a mainly nuclear localized protein with
a widespread expression in embryonic and adult mouse tissues.
CONCLUSION: Our results demonstrate that FAM124B is a potential interacting
partner of a CHD7 and CHD8 containing complex. From the overlapping expression
pattern between Chd7 and Fam124B at murine embryonic day E12.5 and the high
expression of Fam124B in the developing mouse brain, we conclude that Fam124B is
a novel protein possibly involved in the pathogenesis of CHARGE syndrome and
neurodevelopmental disorders.
DOI: 10.1371/journal.pone.0052640
PMCID: PMC3528654
PMID: 23285124 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/22419124 | 1. Epigenetics. 2012 May;7(5):482-91. doi: 10.4161/epi.19741. Epub 2012 May 1.
A human Polycomb isoform lacking the Pc box does not participate to PRC1
complexes but forms protein assemblies and represses transcription.
Völkel P(1), Le Faou P, Vandamme J, Pira D, Angrand PO.
Author information:
(1)Chromatinomics, Interdisciplinary Research Institute, CNRS USR 3078,
Université de Lille 1 Sciences et Technologies, Villeneuve d'Ascq Cedex, France.
Polycomb repression controls the expression of hundreds of genes involved in
development and is mediated by essentially two classes of chromatin-associated
protein complexes. The Polycomb repressive complex 2 (PRC2) trimethylates
histone H3 at lysine 27, an epigenetic mark that serves as a docking site for
the PRC1 protein complex. Drosophila core PRC1 is composed of four subunits:
Polycomb (Pc), Posterior sex combs (Psc), Polyhomeotic (Ph) and Sex combs extra
(Sce). Each of these proteins has multiple orthologs in vertebrates, thus
generating an enormous scope for potential combinatorial diversity. In
particular, mammalian genomes encode five Pc family members: CBX2, CBX4, CBX6,
CBX7 and CBX8. To complicate matters further, distinct isoforms might arise from
single genes. Here, we address the functional role of the two human CBX2
isoforms. Owing to different polyadenylation sites and alternative splicing
events, the human CBX2 locus produces two transcripts: a 5-exon transcript that
encodes the 532-amino acid CBX2-1 isoform that contains the conserved
chromodomain and Pc box and a 4-exon transcript encoding a shorter isoform,
CBX2-2, lacking the Pc box but still possessing a chromodomain. Using
biochemical approaches and a novel in vivo imaging assay, we show that the short
CBX2-2 isoform lacking the Pc box, does not participate in PRC1 protein
complexes, but self-associates in vivo and forms complexes of high molecular
weight. Furthermore, the CBX2 short isoform is still able to repress
transcription, suggesting that Polycomb repression might occur in the absence of
PRC1 formation.
DOI: 10.4161/epi.19741
PMID: 22419124 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22231402 | 1. Nat Struct Mol Biol. 2012 Jan 8;19(2):260-3. doi: 10.1038/nsmb.2196.
Chromodomains read the arginine code of post-translational targeting.
Holdermann I(1), Meyer NH, Round A, Wild K, Sattler M, Sinning I.
Author information:
(1)Heidelberg University Biochemistry Center, Heidelberg, Germany.
Chromodomains typically recruit protein complexes to chromatin and read the
epigenetic histone code by recognizing lysine methylation in histone tails. We
report the crystal structure of the chloroplast signal recognition particle
(cpSRP) core from Arabidopsis thaliana, with the cpSRP54 tail comprising an
arginine-rich motif bound to the second chromodomain of cpSRP43. A twinned
aromatic cage reads out two neighboring nonmethylated arginines and adapts
chromodomains to a non-nuclear function in post-translational targeting.
DOI: 10.1038/nsmb.2196
PMID: 22231402 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17253929 | 1. Genet Test. 2006 Winter;10(4):244-51. doi: 10.1089/gte.2006.10.244.
Screening for CHARGE syndrome mutations in the CHD7 gene using denaturing
high-performance liquid chromatography.
Aramaki M(1), Udaka T, Torii C, Samejima H, Kosaki R, Takahashi T, Kosaki K.
Author information:
(1)Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
Mutations in the CHD7 (chromodomain helicase DNA binding protein 7) gene cause
CHARGE syndrome. At present, however, genetic testing of the CHD7 gene is not
commonly applied in clinical settings because the currently available assays are
technically and financially demanding, mainly because of the size of the gene.
In the present study, we optimized the highly sensitive and specific mutation
scanning method automated denaturing high-performance liquid chromatography
(DHPLC) to analyze the entire coding region of CHD7. The coding region was
amplified by 39 primer pairs, all of which have the same cycling conditions,
aliquoted on a 96-well format polymerase chain reaction (PCR) plate. In this
manner, all of the exons were amplified simultaneously using a single block in a
thermal cycler. We then wrote a computer script to analyze each segment of the
CHD7 gene by DHPLC in a serial manner using conditions that were optimized for
each amplicon. The implementation of this screening method for CHD7 will help
medical geneticists confirm their clinical impressions and provide accurate
genetic counseling to the patients with CHARGE syndrome and their families.
DOI: 10.1089/gte.2006.10.244
PMID: 17253929 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16183644 | 1. J Biol Chem. 2005 Dec 16;280(50):41465-71. doi: 10.1074/jbc.M507077200. Epub
2005 Sep 23.
Three-dimensional solution structures of the chromodomains of cpSRP43.
Sivaraja V(1), Kumar TK, Leena PS, Chang AN, Vidya C, Goforth RL, Rajalingam D,
Arvind K, Ye JL, Chou J, Henry R, Yu C.
Author information:
(1)Department of Chemistry and Biochemistry, University of Arkansas,
Fayetteville, Arkansas 72701, USA.
Chloroplasts contain a unique signal recognition particle (cpSRP). Unlike the
cytoplasmic forms, the cpSRP lacks RNA but contains a conserved 54-kDa GTPase
and a novel 43-kDa subunit (cpSRP43). Recently, three functionally distinct
chromodomains (CDs) have been identified in cpSRP43. In the present study, we
report the three-dimensional solution structures of the three CDs (CD1, CD2, and
CD3) using a variety of triple resonance NMR experiments. The structure of CD1
consists of a triple-stranded beta-sheet segment. The C-terminal helical segment
typically found in the nuclear chromodomains is absent in CD1. The secondary
structural elements in CD2 and CD3 include a triple-stranded antiparallel
beta-sheet and a C-terminal helix. Interestingly, the orientation of the
C-terminal helix is significantly different in the structures of CD2 and CD3.
Critical comparison of the structures of the chromodomains of cpSRP43 with those
found in nuclear chromodomain proteins revealed that the diverse protein-protein
interactions mediated by the CDs appear to stem from the differences that exist
in the surface charge potentials of each CD. Results of isothermal titration
calorimetry experiments confirmed that only CD2 is involved in binding to
cpSRP54. The negatively charged C-terminal helix in CD2 possibly plays a crucial
role in the cpSRP54-cpSRP43 interaction.
DOI: 10.1074/jbc.M507077200
PMID: 16183644 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16613610 | 1. BMC Biol. 2006 Apr 14;4:9. doi: 10.1186/1741-7007-4-9.
Corto and DSP1 interact and bind to a maintenance element of the Scr Hox gene:
understanding the role of Enhancers of trithorax and Polycomb.
Salvaing J(1), Decoville M, Mouchel-Vielh E, Bussière M, Daulny A, Boldyreva L,
Zhimulev I, Locker D, Peronnet F.
Author information:
(1)UMR 7622, CNRS, Université Pierre et Marie Curie, 9, quai Saint-Bernard,
75252 Paris cedex 05, France. j.salvaing@gen.unimaas.nl
BACKGROUND: Polycomb-group genes (PcG) encode proteins that maintain homeotic
(Hox) gene repression throughout development. Conversely, trithorax-group (trxG)
genes encode positive factors required for maintenance of long term Hox gene
activation. Both kinds of factors bind chromatin regions called maintenance
elements (ME). Our previous work has shown that corto, which codes for a
chromodomain protein, and dsp1, which codes for an HMGB protein, belong to a
class of genes called the Enhancers of trithorax and Polycomb (ETP) that
interact with both PcG and trxG. Moreover, dsp1 interacts with the Hox gene Scr,
the DSP1 protein is present on a Scr ME in S2 cells but not in embryos. To
understand better the role of ETP, we addressed genetic and molecular
interactions between corto and dsp1.
RESULTS: We show that Corto and DSP1 proteins co-localize at 91 sites on
polytene chromosomes and co-immunoprecipitate in embryos. They interact directly
through the DSP1 HMG-boxes and the amino-part of Corto, which contains a
chromodomain. In order to search for a common target, we performed a genetic
interaction analysis. We observed that corto mutants suppressed dsp11 sex comb
phenotypes and enhanced AntpScx phenotypes, suggesting that corto and dsp1 are
simultaneously involved in the regulation of Scr. Using chromatin
immunoprecipitation of the Scr ME, we found that Corto was present on this ME
both in Drosophila S2 cells and in embryos, whereas DSP1 was present only in S2
cells.
CONCLUSION: Our results reveal that the proteins Corto and DSP1 are differently
recruited to a Scr ME depending on whether the ME is active, as seen in S2
cells, or inactive, as in most embryonic cells. The presence of a given
combination of ETPs on an ME would control the recruitment of either PcG or TrxG
complexes, propagating the silenced or active state.
DOI: 10.1186/1741-7007-4-9
PMCID: PMC1459216
PMID: 16613610 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21901784 | 1. Dev Dyn. 2011 Oct;240(10):2272-80. doi: 10.1002/dvdy.22722. Epub 2011 Sep 7.
Chd7 plays a critical role in controlling left-right symmetry during zebrafish
somitogenesis.
Jacobs-McDaniels NL(1), Albertson RC.
Author information:
(1)Department of Biology, Syracuse University, Syracuse, New York, USA.
Somitogenesis is a complex process during early vertebrate development involving
interactions between many factors to form a bilateral somite series. A role for
chromatin remodelers in somitogenesis has not yet been demonstrated. Here, we
investigate the function of chromodomain helicase DNA binding protein 7 (chd7)
during zebrafish somitogenesis. We show that Chd7 deficiency leads to asymmetric
segmentation of the presomitic mesoderm (PSM), as revealed by expression of the
somitogenesis genes, cdx1a, dlc, her7, mespa, and ripply1. Moreover, we show
that abrogation of Chd7 results in the loss of asymmetric expression of spaw in
the lateral plate mesoderm, which is consistent with more general laterality
defects. Based on the observation that insufficient Chd7 leads to left-right
asymmetry defects during PSM segmentation, and because CHD7 has been linked to
human spinal deformities, we suggest that zebrafish chd7 morphants may be a good
in vivo model to examine the pathophysiology of these diseases.
Copyright © 2011 Wiley-Liss, Inc.
DOI: 10.1002/dvdy.22722
PMID: 21901784 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18846226 | 1. PLoS Genet. 2008 Oct;4(10):e1000217. doi: 10.1371/journal.pgen.1000217. Epub
2008 Oct 10.
Drosophila Kismet regulates histone H3 lysine 27 methylation and early
elongation by RNA polymerase II.
Srinivasan S(1), Dorighi KM, Tamkun JW.
Author information:
(1)Department of Molecular, Cell, and Developmental Biology, University of
California Santa Cruz, Santa Cruz, CA, USA.
Polycomb and trithorax group proteins regulate cellular pluripotency and
differentiation by maintaining hereditable states of transcription. Many
Polycomb and trithorax group proteins have been implicated in the covalent
modification or remodeling of chromatin, but how they interact with each other
and the general transcription machinery to regulate transcription is not well
understood. The trithorax group protein Kismet-L (KIS-L) is a member of the CHD
subfamily of chromatin-remodeling factors that plays a global role in
transcription by RNA polymerase II (Pol II). Mutations in CHD7, the human
counterpart of kis, are associated with CHARGE syndrome, a developmental
disorder affecting multiple tissues and organs. To clarify how KIS-L activates
gene expression and counteracts Polycomb group silencing, we characterized
defects resulting from the loss of KIS-L function in Drosophila. These studies
revealed that KIS-L acts downstream of P-TEFb recruitment to stimulate
elongation by Pol II. The presence of two chromodomains in KIS-L suggested that
its recruitment or function might be regulated by the methylation of histone H3
lysine 4 by the trithorax group proteins ASH1 and TRX. Although we observed
significant overlap between the distributions of KIS-L, ASH1, and TRX on
polytene chromosomes, KIS-L did not bind methylated histone tails in vitro, and
loss of TRX or ASH1 function did not alter the association of KIS-L with
chromatin. By contrast, loss of kis function led to a dramatic reduction in the
levels of TRX and ASH1 associated with chromatin and was accompanied by
increased histone H3 lysine 27 methylation-a modification required for Polycomb
group repression. A similar increase in H3 lysine 27 methylation was observed in
ash1 and trx mutant larvae. Our findings suggest that KIS-L promotes early
elongation and counteracts Polycomb group repression by recruiting the ASH1 and
TRX histone methyltransferases to chromatin.
DOI: 10.1371/journal.pgen.1000217
PMCID: PMC2563034
PMID: 18846226 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/22039057 | 1. J Biol Chem. 2011 Dec 23;286(51):43984-43993. doi: 10.1074/jbc.M111.282970.
Epub 2011 Oct 28.
Identification of residues in chromodomain helicase DNA-binding protein 1 (Chd1)
required for coupling ATP hydrolysis to nucleosome sliding.
Patel A(1), McKnight JN(1), Genzor P(1), Bowman GD(2).
Author information:
(1)T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore,
Maryland 21218-2685.
(2)T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore,
Maryland 21218-2685. Electronic address: gdbowman@jhu.edu.
Chromatin remodelers are ATP-dependent machines responsible for directionally
shifting nucleosomes along DNA. We are interested in defining which elements of
the chromodomain helicase DNA-binding protein 1 (Chd1) remodeler are necessary
and sufficient for sliding nucleosomes. This work focuses on the polypeptide
segment that joins the ATPase motor to the C-terminal DNA-binding domain. We
identify amino acid positions outside the ATPase motor that, when altered,
dramatically reduce nucleosome sliding ability and yet have only ∼3-fold
reduction in ATPase stimulation by nucleosomes. These residues therefore appear
to play a role in functionally coupling ATP hydrolysis to nucleosome sliding,
and suggest that the ATPase motor requires cooperation with external elements to
slide DNA past the histone core.
DOI: 10.1074/jbc.M111.282970
PMCID: PMC3243530
PMID: 22039057 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21094707 | 1. Eur J Med Genet. 2011 Mar-Apr;54(2):173-6. doi: 10.1016/j.ejmg.2010.11.007.
Epub 2010 Nov 20.
Terminal 4q deletion and 8q duplication in a patient with CHARGE-like features.
Khalifa OA(1), Walter CU, Rahbeeni ZA, Verloes A.
Author information:
(1)Department of Medical Genetics, King Faisal Specialist Hospital and Research
Centre, Riyadh, Saudi Arabia. olagen1@gmail.com
The CHARGE syndrome is a multiple congenital malformation syndrome that usually
results from deletion or heterozygous loss of function mutations of the
chromodomain helicase DNA-binding protein 7 (CHD7) gene at 8q12.1. Besides
CHD7-related cases, some patients with CHARGE-like phenotype have been reported
with chromosomal imbalances. We describe a patient with a pattern of
malformations reminiscent of CHARGE syndrome: choanal atresia, facial
dysmorphism (micrognathia, hypertelorism, epicanthic folds, and depressed, broad
nasal bridge), cardiovascular malformations, cryptorchidism, and developmental
delay. He had duplication 8q and deletion 4q derived from paternal translocation
t(4;8)(q34;q22.1). CHD7 mutation or deletion was excluded. The present report to
the best of our knowledge is the only one describing an unbalanced translocation
t(4;8) and CHARGE-like phenotype.
Copyright © 2010 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.ejmg.2010.11.007
PMID: 21094707 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21979373 | 1. Genes Dev. 2011 Oct 15;25(20):2198-209. doi: 10.1101/gad.17554711. Epub 2011
Oct 6.
Mediator coordinates PIC assembly with recruitment of CHD1.
Lin JJ(1), Lehmann LW, Bonora G, Sridharan R, Vashisht AA, Tran N, Plath K,
Wohlschlegel JA, Carey M.
Author information:
(1)Department of Biological Chemistry, David Geffen School of Medicine at UCLA,
Los Angeles, California 90095, USA.
Murine Chd1 (chromodomain helicase DNA-binding protein 1), a
chromodomain-containing chromatin remodeling protein, is necessary for embryonic
stem (ES) cell pluripotency. Chd1 binds to nucleosomes trimethylated at histone
3 Lys 4 (H3K4me3) near the beginning of active genes but not to bivalent domains
also containing H3K27me3. To address the mechanism of this specificity, we
reproduced H3K4me3- and CHD1-stimulated gene activation in HeLa extracts.
Multidimensional protein identification technology (MuDPIT) and immunoblot
analyses of purified preinitiation complexes (PICs) revealed the recruitment of
CHD1 to naive chromatin but enhancement on H3K4me3 chromatin. Studies in
depleted extracts showed that the Mediator coactivator complex, which controls
PIC assembly, is also necessary for CHD1 recruitment. MuDPIT analyses of
CHD1-associated proteins support the recruitment data and reveal numerous
components of the PIC, including Mediator. In vivo, CHD1 and Mediator are
recruited to an inducible gene, and genome-wide binding of the two proteins
correlates well with active gene transcription in mouse ES cells. Finally,
coimmunoprecipitation of CHD1 and Mediator from cell extracts can be ablated by
shRNA knockdown of a specific Mediator subunit. Our data support a model in
which the Mediator coordinates PIC assembly along with the recruitment of CHD1.
The combined action of the PIC and H3K4me3 provides specificity in targeting
CHD1 to active genes.
DOI: 10.1101/gad.17554711
PMCID: PMC3205589
PMID: 21979373 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21060834 | 1. PLoS One. 2010 Oct 29;5(10):e13732. doi: 10.1371/journal.pone.0013732.
Polycomb CBX7 directly controls trimethylation of histone H3 at lysine 9 at the
p16 locus.
Li Q(1), Wang X, Lu Z, Zhang B, Guan Z, Liu Z, Zhong Q, Gu L, Zhou J, Zhu B, Ji
J, Deng D.
Author information:
(1)Key Laboratory of Carcinogenesis and Translational Research (Ministry of
Education), Department of Etiology, Peking University Cancer Hospital and
Institute, Beijing, China.
BACKGROUND: H3K9 trimethylation (H3K9me3) and binding of PcG repressor complex-1
(PRC1) may play crucial roles in the epigenetic silencing of the p16 gene.
However, the mechanism of the initiation of this trimethylation is unknown.
METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we found that upregulating
the expression of PRC1 component Cbx7 in gastric cancer cell lines MGC803 and
BGC823 led to significantly suppress the expression of genes within the
p16-Arf-p15 locus. H3K9me3 formation was observed at the p16 promoter and
Regulatory Domain (RD). CBX7 and SUV39H2 binding to these regions were also
detectable in the CBX7-stably upregulated cells. CBX7-SUV39H2 complexes were
observed within nucleus in bimolecular fluorescence complementation assay
(BiFC). Mutations of the chromodomain or deletion of Pc-box abolished the
CBX7-binding and H3K9me3 formation, and thus partially repressed the function of
CBX7. SiRNA-knockdown of Suv39h2 blocked the repressive effect of CBX7 on p16
transcription. Moreover, we found that expression of CBX7 in gastric carcinoma
tissues with p16 methylation was significantly lower than that in their
corresponding normal tissues, which showed a negative correlation with
transcription of p16 in gastric mucosa.
CONCLUSION/SIGNIFICANCE: These results demonstrated for the first time, to our
knowledge, that CBX7 could initiate H3K9me3 formation at the p16 promoter.
DOI: 10.1371/journal.pone.0013732
PMCID: PMC2966406
PMID: 21060834 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/18369641 | 1. J Comp Physiol B. 2008 Aug;178(6):729-34. doi: 10.1007/s00360-008-0261-0. Epub
2008 Mar 28.
Epigenetic silencers are enriched in dormant desert frog muscle.
Hudson NJ(1), Lonhienne TG, Franklin CE, Harper GS, Lehnert SA.
Author information:
(1)CSIRO Livestock Industries, Brisbane, Qld, Australia. nick.hudson@csiro.au
Green-striped burrowing frogs, Cyclorana alboguttata, survive droughts by
entering a metabolic depression called aestivation, characterised by a reduction
in resting oxygen consumption by 80%. Aestivation in C. alboguttata is manifest
by transcriptional silencing of skeletal muscle bioenergetic genes, such as NADH
ubiquinone oxidoreductase 1, ATP synthase and superoxide dismutase 2. In this
study, we hypothesised that aestivation is associated with epigenetic change in
frog muscle. We assessed mRNA transcript abundance of seven genes that code for
proteins with established roles in epigenetically-mediated gene silencing
[transcriptional co-repressor SIN3A, DNA (cytosine-5-) methyltransferase 1,
methyl CpG binding protein 2, chromodomain helicase DNA binding protein 4,
histone binding protein rbbp4, histone deacetylase 1 and nuclear receptor
co-repressor 2] using qRT-PCR. These seven genes showed a modest (1.1-3.5-fold)
but coordinated upregulation in 6-month aestivating muscle. This reached
significance for SIN3A and DNA cytosine-5-methyltransferase 1 in standard
pair-wise comparisons (p < 0.05), and the candidates as a whole when analysed by
Fisher's combined probability test (p < 0.01). These data are consistent with
the hypothesis that the transcriptional silencing and metabolic depression that
occurs during seasonal dormancy are associated with chromatin remodelling, and
present a novel example of an environmentally induced epigenetic modification in
an adult vertebrate.
DOI: 10.1007/s00360-008-0261-0
PMID: 18369641 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21146514 | 1. Dev Biol. 2011 Feb 15;350(2):382-92. doi: 10.1016/j.ydbio.2010.12.003. Epub
2010 Dec 10.
A conserved function of the chromatin ATPase Kismet in the regulation of
hedgehog expression.
Terriente-Félix A(1), Molnar C, Gómez-Skarmeta JL, de Celis JF.
Author information:
(1)Centro de Biología Molecular Severo Ochoa, Consejo Superior de
Investigaciones Científicas and Universidad Autónoma de Madrid Cantoblanco,
Madrid, Spain.
The development of the Drosophila melanogaster wing depends on its subdivision
into anterior and posterior compartments, which constitute two independent cell
lineages since their origin in the embryonic ectoderm. The anterior-posterior
compartment boundary is the place where signaling by the Hedgehog pathway takes
place, and this requires pathway activation in anterior cells by ligand
expressed exclusively in posterior cells. Several mechanisms ensure the
confinement of hedgehog expression to posterior cells, including repression by
Cubitus interruptus, the co-repressor Groucho and Master of thick veins. In this
work we identified Kismet, a chromodomain-containing protein of the SNF2-like
family of ATPases, as a novel component of the hedgehog transcriptional
repression mechanism in anterior compartment cells. In kismet mutants, hedgehog
is ectopically expressed in a domain of anterior cells close to the
anterior-posterior compartment boundary, causing inappropriate activation of the
pathway and changes in the development of the central region of the wing. The
contribution of Kismet to the silencing of hedgehog expression is limited to
anterior cells with low levels of the repressor form of Cubitus interruptus. We
also show that knockdown of CHD8, the kismet homolog in Xenopus tropicalis, is
also associated with ectopic sonic hedgehog expression and up-regulation of one
of its target genes in the eye, Pax2, indicating the evolutionary conservation
of Kismet/CHD8 function in negatively controlling hedgehog expression.
Copyright © 2010 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ydbio.2010.12.003
PMID: 21146514 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21596839 | 1. Hum Mol Genet. 2011 Aug 15;20(16):3138-50. doi: 10.1093/hmg/ddr216. Epub 2011
May 19.
Reproductive dysfunction and decreased GnRH neurogenesis in a mouse model of
CHARGE syndrome.
Layman WS(1), Hurd EA, Martin DM.
Author information:
(1)Department of Human Genetics, University of Michigan Medical School, Ann
Arbor, MI 48109-5652, USA.
CHARGE is a multiple congenital anomaly disorder and a common cause of pubertal
defects, olfactory dysfunction, growth delays, deaf-blindness, balance disorders
and congenital heart malformations. Mutations in CHD7, the gene encoding
chromodomain helicase DNA binding protein 7, are present in 60-80% of
individuals with the CHARGE syndrome. Mutations in CHD7 have also been reported
in the Kallmann syndrome (olfactory dysfunction, delayed puberty and
hypogonadotropic hypogonadism). CHD7 is a positive regulator of neural stem cell
proliferation and olfactory sensory neuron formation in the olfactory
epithelium, suggesting that the loss of CHD7 might also disrupt development of
other neural populations. Here we report that female Chd7(Gt/+) mice have delays
in vaginal opening and estrus onset, and erratic estrus cycles. Chd7(Gt/+) mice
also have decreased circulating levels of luteinizing hormone and
follicle-stimulating hormone but apparently normal responsiveness to
gonadotropin-releasing hormone (GnRH) agonist and antagonist treatment. GnRH
neurons in the adult Chd7(Gt/+) hypothalamus and embryonic nasal region are
diminished, and there is decreased cellular proliferation in the embryonic
olfactory placode. Expression levels of GnRH1 and Otx2 in the hypothalamus and
GnRHR in the pituitary are significantly reduced in adult Chd7(Gt/+) mice.
Additionally, Chd7 mutant embryos have CHD7 dosage-dependent reductions in
expression levels of Fgfr1, Bmp4 and Otx2 in the olfactory placode. Together,
these data suggest that CHD7 has critical roles in the development and
maintenance of GnRH neurons for regulating puberty and reproduction.
DOI: 10.1093/hmg/ddr216
PMCID: PMC3140819
PMID: 21596839 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22223433 | 1. Environ Mol Mutagen. 2012 Jan;53(1):44-50. doi: 10.1002/em.20674. Epub 2011
Aug 29.
Chromodomain helicase DNA-binding protein 2 affects the repair of X-ray and
UV-induced DNA damage.
Rajagopalan S(1), Nepa J, Venkatachalam S.
Author information:
(1)Department of Biochemistry and Cellular and Molecular Biology, University of
Tennessee, Knoxville, Tennessee, USA.
Eukaryotic cells have evolved a variety of parallel and redundant DNA damage
response pathways that function in a coordinated fashion to prevent the fixation
of DNA damage as mutations. Despite the wealth of knowledge on DNA damage
signaling on downstream cellular events, the mechanisms of DNA damage
recognition, DNA repair as well as DNA damage signaling in the context of
chromatin is poorly understood. Chromodomain helicase DNA-binding proteins (CHD)
belong to a group of highly conserved chromatin remodeling proteins that are
implicated in regulation of transcription. In an effort to understand the
physiological role of one of the CHD members in a mammalian model system, we
developed a mutant mouse model for the Chd2 gene. The Chd2 mutant mice are
highly susceptible to spontaneous lymphoid tumor formation. In this study, we
present evidence that the Chd2 mutant cells are defective in their ability to
repair DNA damage induced by ionizing and ultraviolet radiation. Consistent with
the role of Chd2 in regulating DNA damage responses, the Chd2 mutant cells are
also sensitive to DNA damaging agents in clonogenic assays. In summary, our data
suggest that the Chd2 protein is involved in regulating the DNA damage responses
at the chromatin level.
Copyright © 2011 Wiley Periodicals, Inc.
DOI: 10.1002/em.20674
PMID: 22223433 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16095617 | 1. J Mol Biol. 2005 Sep 23;352(3):646-55. doi: 10.1016/j.jmb.2005.06.049.
Characterization and functional analysis of CReMM, a novel chromodomain helicase
DNA-binding protein.
Shur I(1), Benayahu D.
Author information:
(1)Department of Cell and Developmental Biology, Sackler School of Medicine,
Tel-Aviv University, Israel.
The present study describes a newly identified protein named CReMM
(chromatin-related mesenchymal modulator). The protein was studied by
bioinformatic means and classified as a member of the third subfamily of
chromodomain helicase DNA-binding proteins (CHD). In silico translation defined
CReMM as a multiple domains protein including two chromodomains, SNF2/ATPase,
helicase C domain and an A/T-DNA-binding domain (DBD). Predicted extensive
post-translation phosphorylation on serine and tyrosine residues was
demonstrated by Western blot in the presence and in the absence of phosphatase
inhibitors using specific antibodies. Immunoprecipitated CReMM disclosed a
DNA-dependent ATPase activity quantified by colorimetric assay. Electrophoresis
mobility-shift assay (EMSA) validated that CReMM binds to A/T-rich DNA. CReMM is
expressed in mesenchymal progenitors, as shown in vitro and in vivo. CReMM
protein structural motifs and proven biochemical activities highlight its role
in chromatin remodeling. Further delineation of the function of this protein
will provide information about its dynamics in transcriptional regulation of
mesenchymal cells.
DOI: 10.1016/j.jmb.2005.06.049
PMID: 16095617 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20950435 | 1. Mol Cancer. 2010 Oct 15;9:277. doi: 10.1186/1476-4598-9-277.
Expression of the neuron-specific protein CHD5 is an independent marker of
outcome in neuroblastoma.
Garcia I(1), Mayol G, Rodríguez E, Suñol M, Gershon TR, Ríos J, Cheung NK,
Kieran MW, George RE, Perez-Atayde AR, Casala C, Galván P, de Torres C, Mora J,
Lavarino C.
Author information:
(1)Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Fundación
Sant Joan de Déu, Barcelona, Spain.
BACKGROUND: The chromodomain, helicase DNA-binding protein 5 (CHD5) is a
potential tumor suppressor gene located on chromosome 1p36, a region recurrently
deleted in high risk neuroblastoma (NB). Previous data have shown that CHD5 mRNA
is present in normal neural tissues and in low risk NB, nevertheless, the
distribution of CHD5 protein has not been explored. The aim of this study was to
investigate CHD5 protein expression as an immunohistochemical marker of outcome
in NB. With this purpose, CHD5 protein expression was analyzed in normal neural
tissues and neuroblastic tumors (NTs). CHD5 gene and protein expression was
reexamined after induction chemotherapy in a subset of high risk tumors to
identify potential changes reflecting tumor response.
RESULTS: We provide evidence that CHD5 is a neuron-specific protein, absent in
glial cells, with diverse expression amongst neuron types. Within NTs, CHD5
immunoreactivity was found restricted to differentiating neuroblasts and
ganglion-like cells, and absent in undifferentiated neuroblasts and stromal
Schwann cells. Correlation between protein and mRNA levels was found, suggesting
transcriptional regulation of CHD5. An immunohistochemical analysis of 90
primary NTs highlighted a strong association of CHD5 expression with favorable
prognostic variables (age at diagnosis <12 months, low clinical stage, and
favorable histology; P < 0.001 for all), overall survival (OS) (P < 0.001) and
event-free survival (EFS) (P < 0.001). Multivariate analysis showed that CHD5
prognostic value is independent of other clinical and biologically relevant
parameters, and could therefore represent a marker of outcome in NB that can be
tested by conventional immunohistochemistry. The prognostic value of CHD5 was
confirmed in an independent, blinded set of 32 NB tumors (P <
0.001).Reactivation of CHD5 expression after induction chemotherapy was observed
mainly in those high risk tumors with induced tumor cell differentiation
features. Remarkably, these NB tumors showed good clinical response and
prolonged patient survival.
CONCLUSIONS: The neuron-specific protein CHD5 may represent a marker of outcome
in NB that can be tested by conventional immunohistochemistry. Re-establishment
of CHD5 expression induced by chemotherapy could be a surrogate marker of
treatment response.
DOI: 10.1186/1476-4598-9-277
PMCID: PMC2992029
PMID: 20950435 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17603073 | 1. J Mol Biol. 2007 Aug 31;371(5):1135-40. doi: 10.1016/j.jmb.2007.06.007. Epub
2007 Jun 9.
Solution structure of the BRK domains from CHD7.
Allen MD(1), Religa TL, Freund SM, Bycroft M.
Author information:
(1)MRC Centre for Protein Engineering, Hills Road, Cambridge, CB2 2QH, UK.
CHD7 is a member of the chromodomain helicase DNA binding domain (CHD) family of
ATP-dependent chromatin remodelling enzymes. It is mutated in CHARGE syndrome, a
multiple congenital anomaly condition. CHD7 is one of a subset of CHD proteins,
unique to metazoans that contain the BRK domain, a protein module also found in
the Brahma/BRG1 family of helicases. We describe here the NMR solution structure
of the two BRK domains of CHD7. Each domain has a compact betabetaalphabeta
fold. The second domain has a C-terminal extension consisting of two additional
helices. The structure differs from those of other domains present in
chromatin-associated proteins.
DOI: 10.1016/j.jmb.2007.06.007
PMID: 17603073 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10199952 | 1. Chromosoma. 1999 Apr;108(1):10-25. doi: 10.1007/s004120050347.
CHD1 interacts with SSRP1 and depends on both its chromodomain and its
ATPase/helicase-like domain for proper association with chromatin.
Kelley DE(1), Stokes DG, Perry RP.
Author information:
(1)Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA.
CHD1, an Mr approximately 200,000 protein that contains a chromodomain (C), an
ATPase/helicase-like domain (H) and a DNA-binding domain (D), was previously
shown to be associated with decompacted interphase chromatin in mammalian cells
and with transcriptionally active puffs and interbands in Drosophila polytene
chromosomes. We now show by transient transfection experiments with genes
expressing wild-type and mutant forms of CHD1 that both the C and H domains are
essential for its proper association with chromatin. We also present evidence
for an in vivo interaction between CHD1 and a novel HMG box-containing protein,
SSRP1, which involves an amino-terminal segment of CHD1 that does not include
the chromodomain. Immunocytochemical analyses indicated that CHD1 and SSRP1
colocalize in both mammalian nuclei and Drosophila polytene chromosomes.
DOI: 10.1007/s004120050347
PMID: 10199952 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22514736 | 1. PLoS One. 2012;7(4):e35376. doi: 10.1371/journal.pone.0035376. Epub 2012 Apr
13.
Structural basis of the chromodomain of Cbx3 bound to methylated peptides from
histone h1 and G9a.
Ruan J(1), Ouyang H, Amaya MF, Ravichandran M, Loppnau P, Min J, Zang J.
Author information:
(1)Hefei National Laboratory for Physical Sciences, Microscale and School of
Life Sciences, University of Science and Technology of China, Hefei, Anhui,
People's Republic of China.
BACKGROUND: HP1 proteins are highly conserved heterochromatin proteins, which
have been identified to be structural adapters assembling a variety of
macromolecular complexes involved in regulation of gene expression, chromatin
remodeling and heterochromatin formation. Much evidence shows that HP1 proteins
interact with numerous proteins including methylated histones, histone
methyltransferases and so on. Cbx3 is one of the paralogues of HP1 proteins,
which has been reported to specifically recognize trimethylated histone H3K9
mark, and a consensus binding motif has been defined for the Cbx3 chromodomain.
METHODOLOGY/PRINCIPAL FINDINGS: Here, we found that the Cbx3 chromodomain can
bind to H1K26me2 and G9aK185me3 with comparable binding affinities compared to
H3K9me3. We also determined the crystal structures of the human Cbx3
chromodomain in complex with dimethylated histone H1K26 and trimethylated
G9aK185 peptides, respectively. The complex structures unveil that the Cbx3
chromodomain specifically bind methylated histone H1K26 and G9aK185 through a
conserved mechanism.
CONCLUSIONS/SIGNIFICANCE: The Cbx3 chromodomain binds with comparable affinities
to all of the methylated H3K9, H1K26 and G9aK185 peptides. It is suggested that
Cbx3 may regulate gene expression via recognizing both histones and non-histone
proteins.
DOI: 10.1371/journal.pone.0035376
PMCID: PMC3325965
PMID: 22514736 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/22242120 | 1. PLoS One. 2011;6(12):e29425. doi: 10.1371/journal.pone.0029425. Epub 2011 Dec
29.
LTR retrotransposons in fungi.
Muszewska A(1), Hoffman-Sommer M, Grynberg M.
Author information:
(1)Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw,
Poland. musze@icm.edu.pl
Transposable elements with long terminal direct repeats (LTR TEs) are one of the
best studied groups of mobile elements. They are ubiquitous elements present in
almost all eukaryotic genomes. Their number and state of conservation can be a
highlight of genome dynamics. We searched all published fungal genomes for
LTR-containing retrotransposons, including both complete, functional elements
and remnant copies. We identified a total of over 66,000 elements, all of which
belong to the Ty1/Copia or Ty3/Gypsy superfamilies. Most of the detected Gypsy
elements represent Chromoviridae, i.e. they carry a chromodomain in the pol ORF.
We analyzed our data from a genome-ecology perspective, looking at the abundance
of various types of LTR TEs in individual genomes and at the highest-copy
element from each genome. The TE content is very variable among the analyzed
genomes. Some genomes are very scarce in LTR TEs (<50 elements), others
demonstrate huge expansions (>8000 elements). The data shows that transposon
expansions in fungi usually involve an increase both in the copy number of
individual elements and in the number of element types. The majority of the
highest-copy TEs from all genomes are Ty3/Gypsy transposons. Phylogenetic
analysis of these elements suggests that TE expansions have appeared
independently of each other, in distant genomes and at different taxonomical
levels. We also analyzed the evolutionary relationships between protein domains
encoded by the transposon pol ORF and we found that the protease is the fastest
evolving domain whereas reverse transcriptase and RNase H evolve much slower and
in correlation with each other.
DOI: 10.1371/journal.pone.0029425
PMCID: PMC3248453
PMID: 22242120 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/22607268 | 1. J Neurochem. 2012 Aug;122(3):487-500. doi: 10.1111/j.1471-4159.2012.07794.x.
Epub 2012 Jun 22.
Repression of transcription of presenilin-1 inhibits γ-secretase independent ER
Ca²⁺ leak that is impaired by FAD mutations.
Das HK(1), Tchedre K, Mueller B.
Author information:
(1)Department of Pharmacology & Neuroscience, University of North Texas Health
Science Center, Fort Worth, Texas 76107, USA. hriday.das@unthsc.edu
Genetic deletion or mutations of presenilin genes (PS1/PS2) cause familial
Alzheimer's disease and calcium (Ca²⁺) signaling abnormalities. PS1/PS2 act as
endoplasmic reticulum (ER) Ca²⁺ leak channels that facilitate passive Ca²⁺ leak
across ER membrane. Studies with PS1/PS2 double knockout (PS1/PS2-DKO) mouse
embryonic fibroblasts showed that PS1/PS2 were responsible for 80% of passive
Ca²⁺ leak from the lumen of endoplasmic reticulum to cytosol. Transient
transfection of the wild type PS1 expression construct increased cytoplasmic
Ca²⁺ as a result of Ca²⁺ leak across ER membrane whereas the FADPS1 (PS1-M146V)
mutation construct alone or in combination with the wild type PS1 expression
construct abrogated Ca²⁺ leak in SK-N-SH cells. Inhibition of basal
c-jun-NH2-terminal kinase (JNK) activity by JNK inhibitor SP600125 repressed PS1
transcription and PS1 protein expression by augmenting p53 protein level in
SK-N-SH cells (Lee and Das 2008). In this report we also showed that repression
of PS1 transcription by JNK inhibitor SP600125 inhibited passive Ca²⁺ leak
across ER membrane which could be rescued by expressing PS1 wild type and not by
expressing FADPS1 (PS1-M146V) under a SP600125 non-responsive promoter.
Treatment of SK-N-SH cells with SP600125 also triggered InsP3R-mediated Ca²⁺
release from the ER by addition of 500 nM bradykinin, an agonist of InsP3
receptor (InsP3R1) without changing the expression of InsP3R1. This data
confirms that SP600125 increases the Ca²⁺ store in the ER by inhibiting
PS1-mediated Ca²⁺ leak across ER membrane. p53, ZNF237 and Chromodomain helicase
DNA-binding protein 3 which are repressors of PS1 transcription, also reduced
Ca²⁺ leak across ER membrane in SK-N-SH cells but γ-secretase inhibitor or
dominant negative γ-secretase-specific PS1 mutant (PS1-D257A) had no significant
effect. Therefore, p53, ZNF237, and Chromodomain helicase DNA-binding protein 3
inhibit the function ER Ca²⁺ leak channels to regulate both ER and cytoplasmic
Ca²⁺ levels and may potentially control Ca²⁺-signaling function of PS1.
© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for
Neurochemistry.
DOI: 10.1111/j.1471-4159.2012.07794.x
PMID: 22607268 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8663349 | 1. J Biol Chem. 1996 Jun 21;271(25):14653-6. doi: 10.1074/jbc.271.25.14653.
Interaction between an integral protein of the nuclear envelope inner membrane
and human chromodomain proteins homologous to Drosophila HP1.
Ye Q(1), Worman HJ.
Author information:
(1)Department of Medicine, College of Physicians and Surgeons, Columbia
University, New York, New York 10032, USA.
At the nuclear envelope in higher eukaryotic cells, the nuclear lamina and the
heterochromatin are adjacent to the inner nuclear membrane, and their attachment
is presumably mediated by integral membrane proteins. In a yeast two-hybrid
screen, the nucleoplasmic domain of lamin B receptor (LBR), an integral protein
of the inner nuclear membrane, associated with two human polypeptides homologous
to Drosophila HP1, a heterochromatin protein involved in position-effect
variegation. LBR fusion proteins bound to HP1 proteins synthesized by in vitro
translation and present in cell lysates. Antibodies against LBR also
co-immunoprecipitated HP1 proteins from cell extracts. LBR can interact with
chromodomain proteins that are highly conserved in eukaryotic species and may
function in the attachment of heterochromatin to the inner nuclear membrane in
cells.
DOI: 10.1074/jbc.271.25.14653
PMID: 8663349 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19205716 | 1. Chromosoma. 2009 Jun;118(3):361-76. doi: 10.1007/s00412-009-0203-y. Epub 2009
Feb 10.
Two new chromodomain-containing proteins that associate with heterochromatin in
Sciara coprophila chromosomes.
Greciano PG(1), Ruiz MF, Kremer L, Goday C.
Author information:
(1)Departamento de Biología Celular y del Desarrollo, Centro de Investigaciones
Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
We report here the molecular and cytological characterization of two proteins,
ScoHET1 and ScoHET2 (for Sciara coprophila heterochromatin), which associate to
constitutive heterochromatin in the dipteran S. coprophila. Both proteins,
ScoHET1 of 37 kDa and ScoHET2 of 44 kDa, display two chromodomain motifs that
contain the conserved residues essential for the recognition of methylated
histone H3 at lysine 9. We raised antibodies to analyze the chromosomal location
of ScoHET1 and ScoHET2 in somatic and germline cells. In S. coprophila polytene
chromosomes, both proteins associate to the pericentromeric regions and to the
heterochromatic subterminal bands of the chromosomes. In germinal nuclei,
ScoHET1 and ScoHET2 proteins distribute to the heterochromatic regions of the
regular chromosome complement and are abundantly present along the
heterochromatic germline-limited "L" chromosomes. We investigated histone
methylation modifications and found that all heterochromatic regions enriched in
ScoHET1/ScoHET2 proteins exhibit high levels of di- and tri-methylated histone
H3 at lysine 9. Taken together, our results support that the association of
ScoHET1/ScoHET2 to heterochromatin is mediated by histone H3K9 methylation.
Using 5-methylcytosine antibodies, we proved the cytological detection of DNA
methylation in S. coprophila. From our observations in L germline chromosomes,
heterochromatin in S. coprophila is highly enriched in DNA 5-methylcytosine
residues.
DOI: 10.1007/s00412-009-0203-y
PMID: 19205716 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22073269 | 1. PLoS One. 2011;6(11):e27118. doi: 10.1371/journal.pone.0027118. Epub 2011 Nov
4.
Discovery of EST-SSRs in lung cancer: tagged ESTs with SSRs lead to differential
amino acid and protein expression patterns in cancerous tissues.
Bakhtiarizadeh MR(1), Ebrahimi M, Ebrahimie E.
Author information:
(1)Department of Animal Science, University of Tehran, Karaj, Iran.
Tandem repeats are found in both coding and non-coding sequences of higher
organisms. These sequences can be used in cancer genetics and diagnosis to
unravel the genetic basis of tumor formation and progression. In this study, a
possible relationship between SSR distributions and lung cancer was studied by
comparative analysis of EST-SSRs in normal and lung cancerous tissues. While the
EST-SSR distribution was similar between tumorous tissues, this distribution was
different between normal and tumorous tissues. Trinucleotides tandem repeats
were highly different; the number of trinucleotides in ESTs of lung cancer was 3
times higher than normal tissue. Significant negative correlation between normal
and cancerous tissue showed that cancerous tissue generates different types of
trinucleotides. GGC and CGC were the more frequent expressed trinucleotides in
cancerous tissue, but these SSRs were not expressed in normal tissue. Similar to
the EST level, the expression pattern of EST-SSRs-derived amino acids was
significantly different between normal and cancerous tissues. Arg, Pro, Ser,
Gly, and Lys were the most abundant amino acids in cancerous tissues, and Leu,
Cys, Phe, and His were significantly more abundant in normal tissues than in
cancerous tissues. Next, the putative functions of triplet SSR-containing genes
were analyzed. In cancerous tissue, EST-SSRs produce different types of
proteins. Chromodomain helicase DNA binding proteins were one of the major
protein products of EST-SSRs in the cancerous library, while these proteins were
not produced from EST-SSRs in normal tissue. For the first time, the findings of
this study confirmed that EST-SSRs in normal lung tissues are different than in
unhealthy tissues, and tagged ESTs with SSRs cause remarkable differences in
amino acid and protein expression patterns in cancerous tissue. We suggest that
EST-SSRs and EST-SSRs differentially expressed in cancerous tissue may be
suitable candidate markers for lung cancer diagnosis and prediction.
DOI: 10.1371/journal.pone.0027118
PMCID: PMC3208562
PMID: 22073269 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/20860631 | 1. Andrologia. 2010 Oct;42(5):326-30. doi: 10.1111/j.1439-0272.2009.00994.x.
CHARGE syndrome as unusual cause of hypogonadism: endocrine and molecular
evaluation.
Foppiani L(1), Maffè A, Forzano F.
Author information:
(1)Endocrinology, Galliera Hospital, Genova, Italy. luca.foppiani@galliera.it
Coloboma, heart defect, atresia choanae, retarded growth and development,
genital hypoplasia, ear anomalies (CHARGE) syndrome is a genetic syndrome in
which hypogonadism is a frequent feature. A causative mutation within the
chromodomain helicase DNA-binding protein-7 gene, which plays an important role
in the embryonic development, is present in 2/3 of affected patients. We
describe the clinical, hormonal and molecular characteristics of a young man
from Ecuador who was diagnosed as having CHARGE syndrome at an adult age. The
patient showed several phenotypic features of the syndrome, associated with a
prepubertal state and cryptorchidism; hypogonadotrophic hypogonadism with
undetectable testosterone levels not responsive to hCG testing and severe
osteoporosis were ascertained. Molecular evaluation of the CHD7 gene showed the
novel frameshift truncating heterozygous mutation p.Tyr1046Glyfs*23 in exon 12.
Magnetic resonance imaging revealed mild hypoplasia of the pituitary gland and
hypoplasia of the posterior cranial fossa. Parenteral testosterone therapy led
to sexual development over time and, in combination with diphophonate therapy
and calcium-vitamin D supplementation, significantly improved bone
mineralisation. Early proper hormonal treatment of hypogonadism in patients with
complex genetic syndromes is important to achieve normal sexual maturation,
improve quality of life and avoid significant comorbidities, such as
osteoporosis.
© 2010 Blackwell Verlag GmbH.
DOI: 10.1111/j.1439-0272.2009.00994.x
PMID: 20860631 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22691070 | 1. Plant J. 2012 Oct;72(1):142-53. doi: 10.1111/j.1365-313X.2012.05072.x. Epub
2012 Jul 30.
The sunflower (Helianthus annuus L.) genome reflects a recent history of biased
accumulation of transposable elements.
Staton SE(1), Bakken BH, Blackman BK, Chapman MA, Kane NC, Tang S, Ungerer MC,
Knapp SJ, Rieseberg LH, Burke JM.
Author information:
(1)Department of Genetics, University of Georgia, Athens, GA 30602, USA.
Aside from polyploidy, transposable elements are the major drivers of genome
size increases in plants. Thus, understanding the diversity and evolutionary
dynamics of transposable elements in sunflower (Helianthus annuus L.),
especially given its large genome size (∼3.5 Gb) and the well-documented cases
of amplification of certain transposons within the genus, is of considerable
importance for understanding the evolutionary history of this emerging model
species. By analyzing approximately 25% of the sunflower genome from random
sequence reads and assembled bacterial artificial chromosome (BAC) clones, we
show that it is composed of over 81% transposable elements, 77% of which are
long terminal repeat (LTR) retrotransposons. Moreover, the LTR retrotransposon
fraction in BAC clones harboring genes is disproportionately composed of
chromodomain-containing Gypsy LTR retrotransposons ('chromoviruses'), and the
majority of the intact chromoviruses contain tandem chromodomain duplications.
We show that there is a bias in the efficacy of homologous recombination in
removing LTR retrotransposon DNA, thereby providing insight into the mechanisms
associated with transposable element (TE) composition in the sunflower genome.
We also show that the vast majority of observed LTR retrotransposon insertions
have likely occurred since the origin of this species, providing further
evidence that biased LTR retrotransposon activity has played a major role in
shaping the chromatin and DNA landscape of the sunflower genome. Although our
findings on LTR retrotransposon age and structure could be influenced by the
selection of the BAC clones analyzed, a global analysis of random sequence reads
indicates that the evolutionary patterns described herein apply to the sunflower
genome as a whole.
© 2012 The Authors. The Plant Journal © 2012 Blackwell Publishing Ltd.
DOI: 10.1111/j.1365-313X.2012.05072.x
PMID: 22691070 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22083958 | 1. Mol Cell Biol. 2012 Jan;32(2):501-12. doi: 10.1128/MCB.06409-11. Epub 2011 Nov
14.
Histone H1 recruitment by CHD8 is essential for suppression of the Wnt-β-catenin
signaling pathway.
Nishiyama M(1), Skoultchi AI, Nakayama KI.
Author information:
(1)Department of Molecular and Cellular Biology, Medical Institute of
Bioregulation, Kyushu University, Fukuoka, Japan.
Members of the chromodomain helicase DNA-binding (CHD) family of proteins are
thought to regulate gene expression. Among mammalian CHD proteins, CHD8 was
originally isolated as a negative regulator of the Wnt-β-catenin signaling
pathway that binds directly to β-catenin and suppresses its transactivation
activity. The mechanism by which CHD8 inhibits β-catenin-dependent transcription
has been unclear, however. Here we show that CHD8 promotes the association of
β-catenin and histone H1, with formation of the trimeric complex on chromatin
being required for inhibition of β-catenin-dependent transactivation. A CHD8
mutant that lacks the histone H1 binding domain did not show such inhibitory
activity, indicating that histone H1 recruitment is essential for the inhibitory
effect of CHD8. Furthermore, either depletion of histone H1 or expression of a
dominant negative mutant of this protein resulted in enhancement of the response
to Wnt signaling. These observations reveal a new mode of regulation of the Wnt
signaling pathway by CHD8, which counteracts β-catenin function through
recruitment of histone H1 to Wnt target genes. Given that CHD8 is expressed
predominantly during embryogenesis, it may thus contribute to setting a
threshold for responsiveness to Wnt signaling that operates in a
development-dependent manner.
DOI: 10.1128/MCB.06409-11
PMCID: PMC3255766
PMID: 22083958 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19029895 | 1. Nat Struct Mol Biol. 2008 Dec;15(12):1318-25. doi: 10.1038/nsmb.1520. Epub
2008 Nov 23.
The MSL3 chromodomain directs a key targeting step for dosage compensation of
the Drosophila melanogaster X chromosome.
Sural TH(1), Peng S, Li B, Workman JL, Park PJ, Kuroda MI.
Author information:
(1)Harvard-Partners Center for Genetics and Genomics, Division of Genetics,
Department of Medicine, Brigham & Women's Hospital, 77 Avenue Louis Pasteur,
Boston, Massachusetts 02115, USA.
The male-specific lethal (MSL) complex upregulates the single male X chromosome
to achieve dosage compensation in Drosophila melanogaster. We have proposed that
MSL recognition of specific entry sites on the X is followed by local targeting
of active genes marked by histone H3 trimethylation (H3K36me3). Here we analyze
the role of the MSL3 chromodomain in the second targeting step. Using ChIP-chip
analysis, we find that MSL3 chromodomain mutants retain binding to chromatin
entry sites but show a clear disruption in the full pattern of MSL targeting in
vivo, consistent with a loss of spreading. Furthermore, when compared to wild
type, chromodomain mutants lack preferential affinity for nucleosomes containing
H3K36me3 in vitro. Our results support a model in which activating complexes,
similarly to their silencing counterparts, use the nucleosomal binding
specificity of their respective chromodomains to spread from initiation sites to
flanking chromatin.
DOI: 10.1038/nsmb.1520
PMCID: PMC2636508
PMID: 19029895 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21972924 | 1. J Periodontal Res. 2012 Apr;47(2):180-7. doi:
10.1111/j.1600-0765.2011.01419.x. Epub 2011 Oct 5.
Restricted expression of chromatin remodeling associated factor Chd3 during
tooth root development.
Date Y(1), Yokoyama Y, Kondo H, Kuroda S, Ohya K, Ota MS, Iseki S, Kasugai S.
Author information:
(1)Section of Oral Implantology and Regenerative Dental Medicine, Tokyo Medical
and Dental University, Bunkyo-ku, Tokyo, Japan.
BACKGROUND AND OBJECTIVE: The tooth root is one of the critical parts to
maintain tooth function; however, the molecular mechanisms of root development
remain unknown. We aimed to identify specific factors for root morphogenesis
using a newly developed experimental system.
MATERIAL AND METHODS: Tentative cementoblasts and periodontal ligament cells
from mouse mandibular molars were isolated using laser capture microdissection.
More than 500 cementoblasts and periodontal ligament cells were separately
captured. After RNA extraction and amplification, mRNA expression in isolated
cementoblasts was compared with that of periodontal ligament cells by cDNA
microarray analysis. Then, putative cementoblast-specific genes were subjected
to in situ hybridization analysis to confirm the results in mouse mandible.
RESULTS: Approximately 2000 genes were differentially expressed between these
tissues. Among those genes, zinc finger helicase (ZFH), also termed
chromodomain-helicase-DNA-binding protein 3 (Chd3), was one of the highly
expressed transcripts in tentative cementoblasts. In situ hybridization revealed
that ZFH/Chd3 was strongly expressed in Hertwig's epithelial root sheath rather
than in cementum. Moreover, its expression disappeared when root formation was
advanced in the first molar. In contrast, Chd3 was continuously expressed in
dental epithelial cells of the cervical loop, in which root extension is never
terminated.
CONCLUSION: These results suggest that ZFH/Chd3 might play an important role in
tooth root development and subsequent cementogenesis.
© 2011 John Wiley & Sons A/S.
DOI: 10.1111/j.1600-0765.2011.01419.x
PMID: 21972924 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22235338 | 1. PLoS One. 2012;7(1):e29750. doi: 10.1371/journal.pone.0029750. Epub 2012 Jan
3.
MicroRNA-211 expression promotes colorectal cancer cell growth in vitro and in
vivo by targeting tumor suppressor CHD5.
Cai C(1), Ashktorab H, Pang X, Zhao Y, Sha W, Liu Y, Gu X.
Author information:
(1)Department of Gastroenterology, Peking University People's Hospital, Beijing,
People's Republic of China.
BACKGROUND: Chromodomain-helicase-DNA-binding protein 5 (CHD5) is a newly
identified tumor suppressor that is frequently downregulated in a variety of
human cancers. Our previous work revealed that the low expression of CHD5 in
colorectal cancer is correlated with CHD5 promoter CpG island hypermethylation.
In this study, we investigated the effect of microRNA-211 (miR-211)-regulated
CHD5 expression on colorectal tumorigenesis.
METHODOLOGY/PRINCIPAL FINDINGS: miR-211 was predicted to target CHD5 by
TargetScan software analysis. A stably expressing exogenous miR-211 colorectal
cancer cell line (HCT-116(miR-211)) was generated using lentiviral transduction
and used as a model for in vitro and in vivo studies. The expression level of
miR-211 in HCT-116(miR-211) cells was upregulated by 16-fold compared to vector
control cells (HCT-116(vector)). Exogenous miR-211 directly binds to the
3'-untranslated region (3'-UTR) of CHD5 mRNA, resulting in a 50% decrease in
CHD5 protein level in HCT-116(miR-211) cells. The levels of cell proliferation,
tumor growth, and cell migration of HCT-116(miR-211) cells were significantly
higher than HCT-116(vector) cells under both in vitro and in vivo conditions, as
determined using the methods of MTT, colony formation, flow cytometry, scratch
assay, and tumor xenografts, respectively. In addition, we found that enforced
expression of miR-211 in HCT-116 cells was able to alter p53 pathway-associated
regulatory proteins, such as MDM2, Bcl-2, Bcl-xL, and Bax.
CONCLUSION/SIGNIFICANCE: Our results demonstrate that CHD5 is a direct target of
miR-211 regulation. Enforced expression of miR-211 promotes tumor cell growth at
least in part by downregulating the expression level of the CHD5 tumor
suppressor. Our results provide a better understanding of the association of
between miR-211-regulated CHD5 expression and CHD5 function in colorectal
tumorigenesis.
DOI: 10.1371/journal.pone.0029750
PMCID: PMC3250477
PMID: 22235338 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |