CHD7 Targets Active Gene Enhancer Elements to Modulate ES Cell-Specific Gene Expression

abstract: ...CHD7 is one of nine members of the chromodomain helicase DNAbinding domain family of ATPdependent 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 (ChIPSeq) 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 ChIPseq 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 ESspecific 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.

...PLoS Genet PLoS Genet plos plosgen PLoS Genetics 1553-7390 1553-7404 Public Library of Science San Francisco, USA 20657823 2904778 09-PLGE-RA-2166R3 10.1371/journal.pgen.1001023 Research Article Genetics and Genomics/Epigenetics Genetics and Genomics/Gene Expression Genetics and Genomics/Gene Function Genetics and Genomics/Genetics of Disease CHD7 Targets Active Gene Enhancer Elements to Modulate ES Cell-Specific Gene Expression CHD7 Modulates ES-Specific Expression Schnetz Michael P. 1

... under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. Chromatin Remodeling in Development and Disease: Focus on CHD7 CHD7 is one of nine members of the chromodomain helicase DNAbinding domain family of ATPdependent 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 (ChIPSeq) 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 ChIPseq 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 ESspecific 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. Author Summary The gene encoding chromodomain helicase DNAbinding protein 7 ( CHD7 ) is required for normal mammalian development. In humans, genetic mutations in CHD7 lead to CHARGE syndrome, a disorder characterized by multiple birth defects. In previous studies, CHD7 was shown to localize to the cell nucleus and bind to specific sites on chromatin. However, the genome-wide distribution of CHD7 on chromatin and its function are not known. Here, we identified 10,483 sites on chromatin bound by CHD7 in mouse embryonic stem cells. Many of these sites are gene enhancer elements suspected to be involved in turning on genes. We show CHD7 functions at these loci to fine-tune the levels of genes that are specifically expressed in mouse ES cells. This modulation is mediated through several proteins that bind together with CHD7

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Gene: CHD7 - chromodomain helicase DNA binding protein 7 - (NCBI)

Protein : 2v0e

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