Transcription-coupled recruitment of human CHD1 and CHD2 influences chromatin accessibility and histone H3 and H3.3 occupancy at active chromatin regions

Abstract

BackgroundCHD1 and CHD2 chromatin remodeling enzymes play important roles in development, cancer and differentiation. At a molecular level, the mechanisms are not fully understood but include transcriptional regulation, nucleosome organization and turnover.ResultsHere we show human CHD1 and CHD2 enzymes co-occupy active chromatin regions associated with transcription start sites (TSS), enhancer like regions and active tRNA genes. We demonstrate that their recruitment is transcription-coupled. CHD1 and CHD2 show distinct binding profiles across active TSS regions. Depletion of CHD1 influences chromatin accessibility at TSS and enhancer-like chromatin regions. CHD2 depletion causes increased histone H3 and reduced histone variant H3.3 occupancy.ConclusionsWe conclude that transcription-coupled recruitment of CHD1 and CHD2 occurs at transcribed gene TSSs and at intragenic and intergenic enhancer-like sites. The recruitment of CHD1 and CHD2 regulates the architecture of active chromatin regions through chromatin accessibility and nucleosome disassembly.Electronic supplementary materialThe online version of this article (doi:10.1186/1756-8935-8-4) contains supplementary material, which is available to authorized users.

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“…The MLL3/4 methyltransferase complexes control H3K4 methylation at enhancers (Hu et al., 2013), but MLL3 is detectable by ChIP at Egr1 , suggesting that it may act directly to influence H3K4me3 accumulation there. CHD2 is found at many TSS regions (Ernst and Kellis, 2013, Siggens et al., 2015) and may be required for signal-induced nucleosome remodeling events, which are known to accompany IE gene activation (Riffo-Campos et al., 2015). …”

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“…H3.3 is also present at the promoters of developmentally regulated genes, which are typically silenced or weakly transcribed in embryonic stem cells (Banaszynski et al, 2013). H3.3 is expressed throughout the cell cycle and it has been argued that Chd1 and 2 deposit it into chromatin (Konev et al, 2007; Siggens et al, 2015). H3.3 deposition is facilitated by the histone chaperones Hira and Atrx/Daxx (Banaszynski et al, 2013; Goldberg et al, 2010; Szenker et al, 2011).…”

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“…Simultaneously, Chd1 expression is compromised, and there is also less Chd1 bound at the promoters of Oct4 and Nanog since these regions have less H3K4me3 compared to undifferentiated ES cells, and Chd1 is known to bind H3K4me3 via its CHROMO domains. A separate study found that H3K4me3 is not sufficient for recruiting CHD1 to promoters; instead, CHD1 is recruited to target loci through its interaction with components of the transcriptional machinery in an activation-dependent manner where it regulates H3/H3.3 occupancy and chromatin accessibility at transcriptional start sites of its target genes (Siggens et al 2015). …”

“…For example, CHD2 may also be hormone responsive, as human chorionic gonadotropin (hCG) that is released systemically during pregnancy causes transcriptional induction of CHD2, which has been proposed to along with other chromatin regulators to prevent breast cancer (Russo and Russo 2012). CHD2 also regulates H3/H3.3 occupancy (Siggens et al 2015). As is the case for CHD1 (and other CHDs, see below), colorectal tumors with high microsatellite instability have CHD2 mutations (Kim et al 2011).…”