H2A.Z Facilitates Access of Active and Repressive Complexes to Chromatin in Embryonic Stem Cell Self-Renewal and Differentiation

Abstract

Summary Chromatin modifications have been implicated in the self-renewal and differentiation of embryonic stem cells (ESCs). However, the function of histone variant H2A.Z in ESCs remains unclear. We show that H2A.Z is highly enriched at promoters and enhancers and is required for both efficient self-renewal and differentiation of murine ESCs. H2A.Z deposition leads to an abnormal nucleosome structure, decreased nucleosome occupancy and increased chromatin accessibility. In self-renewing ESCs, knockdown of H2A.Z compromises OCT4 binding to its target genes and leads to decreased binding of MLL complexes to active genes and of PRC2 complex to repressed genes. During differentiation of ESCs, inhibition of H2A.Z also compromises RA-induced RARα binding, activation of differentiation markers and the repression of pluripotency genes. We propose that H2A.Z mediates such contrasting activities by acting as a ‘general facilitator’ that generates access for a variety of complexes both activating and repressive.

BAF250a Protein Regulates Nucleosome Occupancy and Histone Modifications in Priming Embryonic Stem Cell Differentiation

“…However, in our study, we found a nucleosome located at nucleosome-free regions. These nucleosomes were also found in other limited digestion studies (27)(28)(29). The observation of these nucleosomes indicates that these nucleosomes are most accessible and can be further digested with higher MNase concentrations.…”

Comprehensive profiling reveals mechanisms of SOX2-mediated cell fate specification in human ESCs and NPCs

“…H2A.Z was initially reported to co-occupy promoters of developmentally important genes with PRC2 component Suz12 in mESCs and repress the expression of these genes [51]. Moreover, H2A.Z was reported to be required for efficient binding of Oct4 to its targets in mESCs [24] and to provide a binding platform for pioneer factor Foxa2 to bind the promoter of genes activated during endoderm differentiation [22,52]. Another histone variant H2A.X was also showed to occupy Cdx2-binding sites on extraembryonic genes and to repress their induction in mESCs and mouse induced pluripotent stem cells [53].…”

“…Interestingly, PRC2, responsible for the generation of repressive histone mark H3K27me3, and core pluripotency factors (OCT4, SOX2 and NANOG) were shown to co-occupy a significant proportion of developmental genes in hESCs [21], suggesting a link between the binding of pluripotency factors and the deposition of H3K27me3. Moreover, histone variant H2A.Z was also shown to enrich at PRC2 target genes in ESCs and to function in organizing the pluripotent chromatin state [22,[24][25][26]. However, how pluripotency factors participate in the preservation of genomic plasticity and coordinate with chromatin regulators to repress developmentally poised genes in hESCs has not been clearly answered.…”

How life changes itself: The Read–Write (RW) genome

“…For example, H2AX occurs in phosphorylated form at sites of double-strand DNA breakage [76], H2AZ characterizes the genomes of pluripotent cells [77][78][79], and centromeres contain a specialized histone called CENH3 [80,81].…”