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dc.contributor.author Schnetz, MP
dc.contributor.author Handoko, L
dc.contributor.author Akhtar-Zaidi, B
dc.contributor.author Bartels, CF
dc.contributor.author Pereira, CF
dc.contributor.author Fisher, AG
dc.contributor.author Adams, DJ
dc.contributor.author Flicek, P
dc.contributor.author Crawford, GE
dc.contributor.author Laframboise, T
dc.contributor.author Tesar, P
dc.contributor.author Wei, CL
dc.contributor.author Scacheri, PC
dc.date.accessioned 2011-06-21T17:31:21Z
dc.date.issued 2010-07-01
dc.identifier.citation PLoS genetics, 2010, 6 (7)
dc.identifier.uri http://hdl.handle.net/10161/4475
dc.description.abstract CHD7 is one of nine members of the chromodomain helicase DNA-binding domain family of ATP-dependent chromatin remodeling enzymes found in mammalian cells. De novo mutation of CHD7 is a major cause of CHARGE syndrome, a genetic condition characterized by multiple congenital anomalies. To gain insights to the function of CHD7, we used the technique of chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-Seq) to map CHD7 sites in mouse ES cells. We identified 10,483 sites on chromatin bound by CHD7 at high confidence. Most of the CHD7 sites show features of gene enhancer elements. Specifically, CHD7 sites are predominantly located distal to transcription start sites, contain high levels of H3K4 mono-methylation, found within open chromatin that is hypersensitive to DNase I digestion, and correlate with ES cell-specific gene expression. Moreover, CHD7 co-localizes with P300, a known enhancer-binding protein and strong predictor of enhancer activity. Correlations with 18 other factors mapped by ChIP-seq in mouse ES cells indicate that CHD7 also co-localizes with ES cell master regulators OCT4, SOX2, and NANOG. Correlations between CHD7 sites and global gene expression profiles obtained from Chd7(+/+), Chd7(+/-), and Chd7(-/-) ES cells indicate that CHD7 functions at enhancers as a transcriptional rheostat to modulate, or fine-tune the expression levels of ES-specific genes. CHD7 can modulate genes in either the positive or negative direction, although negative regulation appears to be the more direct effect of CHD7 binding. These data indicate that enhancer-binding proteins can limit gene expression and are not necessarily co-activators. Although ES cells are not likely to be affected in CHARGE syndrome, we propose that enhancer-mediated gene dysregulation contributes to disease pathogenesis and that the critical CHD7 target genes may be subject to positive or negative regulation.
dc.language.iso en_US en_US
dc.relation.ispartof PLoS genetics
dc.title CHD7 targets active gene enhancer elements to modulate ES cell-specific gene expression.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US
duke.date.pubdate 2010-7-0 en_US
duke.description.endpage e1001023 en_US
duke.description.issue 7 en_US
duke.description.startpage e1001023 en_US
duke.description.volume 6 en_US
dc.relation.journal Plos Genetics en_US
pubs.issue 7
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Molecular Genetics and Microbiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pediatrics
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pediatrics/Pediatrics, Medical Genetics
pubs.publication-status Published
pubs.volume 6
dc.identifier.eissn 1553-7404

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