CHD7 targets active gene enhancer elements to modulate ES cell-specific gene expression.
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.
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https://hdl.handle.net/10161/4475Collections
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Show full item recordScholars@Duke
Gregory E. Crawford
Professor in Pediatrics
My research involves identifying gene regulatory elements across the genome to help
us understand how chromatin structure dictates cell function and fate. For the last
30 years, mapping chromatin accessible sites has been the gold standard method to
identify the location of active regulatory elements, including promoters, enhancers,
silencers, and locus control regions. I have developed technologies that can identify
most DNase I hypersensitive sites from potentially any cell type from any speci

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