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.

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

“…The wide range of phenotypes associated with CHARGE syndrome is thought to primarily be the consequence of tissue‐specific dysregulation of gene transcription during development (Basson & van Ravenswaaij‐Arts, 2015; Engelen et al, 2011; Schnetz et al, 2009; Schnetz et al, 2010). It has been proposed that mutations or variants in genes that are regulated by or otherwise interact with CHD7 may contribute to, or modify, the phenotypic outcome of a mutation in CHD7 (Basson, 2014).…”

The Trithorax Group Protein Ash2l Is Essential for Pluripotency and Maintaining Open Chromatin in Embryonic Stem Cells

“…Among Ash2l target genes are several known open chromatin regulators, including Chd1, Chd7, Kdm4b, Kdm4c, and c-Myc (26,27,29,(62)(63)(64). These factors have been shown to maintain open chromatin through chromatin remodeling, transcriptional control, and H3K9me3 demethylation (26,27,29,(62)(63)(64). We provide evidence here that Chd7, c-Myc, and Given the complexity and dynamic nature of ES cell selfrenewal and open chromatin maintenance, alterations in the composition and activity of Ash2l complexes during ES cell differentiation warrant further investigation.…”

“…Genome-wide localization analysis of Chd1 shows its strong correlation with enrichment of Pol II and H3K4me3 but not bivalent domains in ES cells (26). Chd7, another Chd family member, co-localizes with Oct4, Nanog, Sox2, and p300 at enhancers of actively transcribed genes, indicating a likely role for Chd7 in promoting open chromatin in ES cells (29). For induced pluripotent stem cell generation, c-Myc appears to promote active transcription and open chromatin by increasing proliferation and opposing differentiation (30 -32).…”

Duplication 8q12: confirmation of a novel recognizable phenotype with duane retraction syndrome and developmental delay

“…22 The protein products of the CHD7 gene can modulate genes in either the positive or negative direction, suggesting that gene dosage of the CHD7 gene may have an effect on the regulated genes. 23 To our knowledge, no information is available in the literature regarding pathological effects secondary to overexpression of the CHD7 gene. However, loss of function of this gene leads to CHARGE syndrome 24 possibly by dysregulation of tissue-specific gene expression.…”