Chromatin remodeling and bivalent histone modifications in embryonic stem cells

Abstract

Pluripotent embryonic stem cells (ESCs) are characterized by distinct epigenetic features including a relative enrichment of histone modifications related to active chromatin. Among these is tri-methylation of lysine 4 on histone H3 (H3K4me3). Several thousands of the H3K4me3-enriched promoters in pluripotent cells also contain a repressive histone mark, namely H3K27me3, a situation referred to as "bivalency". While bivalent promoters are not unique to pluripotent cells, they are relatively enriched in these cell types, largely marking developmental and lineage-specific genes which are silent but poised for immediate action. The H3K4me3 and H3K27me3 modifications are catalyzed by lysine methyltransferases which are usually found within, although not entirely limited to, the Trithorax group (TrxG) and Polycomb group (PcG) protein complexes, respectively, but these do not provide selective bivalent specificity. Recent studies highlight the family of ATPdependent chromatin remodeling proteins as regulators of bivalent domains. Here, we discuss bivalency in general, describe the machineries that catalyze bivalent chromatin domains, and portray the emerging connection between bivalency and the action of different families of chromatin remodelers, namely INO80, esBAF, and NuRD, in pluripotent cells. We posit that chromatin remodeling proteins may enable "bivalent specificity", often selectively acting on, or selectively depleted from, bivalent domains.

Targeting the epigenome in malignant pleural mesothelioma

“…Although often associated with promoter hypermethylation, polycomb-mediated gene silencing may occur independent of DNA methylation (86,87), typically in the context of bivalent chromatin, exhibiting occupancy of PcG proteins and simultaneous activation (H3K4Me3) and repressive (H3K27Me3) histone marks. Frequently observed in stem cells, bivalent chromatin maintains differentiation-related genes in a repressed, but poised state for rapid activation or permanent silencing depending on the differentiation signal (88,89 (90). Collectively, these experiments were the first demonstration that EZH2 is over-expressed in MPM, and that PRC-2 is a potential therapeutic target in these neoplasms.…”

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

“…Thus, methylation of lysine 27 (H3K27) or lysine 9 (H3K9) on histone H3, or of lysine 20 on histone 4 (H4K20), is associated with silenced chromatin [2,3]. In contrast, methylation of lysine 4 on histone 4 (H3K4) is primarily associated with gene activation [4], and methylation of lysine 36 on histone H3 (H3K36) generally regulates transcriptional elongation [5]. Moreover, so-called bivalent promoters contain both active (H3K4me3) and repressive (H3K27me3) histone methylation [5].…”

“…In contrast, methylation of lysine 4 on histone 4 (H3K4) is primarily associated with gene activation [4], and methylation of lysine 36 on histone H3 (H3K36) generally regulates transcriptional elongation [5]. Moreover, so-called bivalent promoters contain both active (H3K4me3) and repressive (H3K27me3) histone methylation [5]. Genes controlled by bivalent promoters, like the Hox genes, are in a poised intermediate state in stem cells.…”

“…Genes controlled by bivalent promoters, like the Hox genes, are in a poised intermediate state in stem cells. They can be activated or repressed during stem cell differentiation by removing H3K27me3 or H3K4me3, respectively [5]. It was long believed that methylation is an irreversible modification, since the half-lives of histones and the methyl-lysine residues within them are the same [6,7]-in other words, if it is an irreversible modification, the methyl group would be "removed" by natural histone turnover or by dilution after DNA replication.…”

From Flies to Mice: The Emerging Role of Non-Canonical PRC1 Members in Mammalian Development

“…The main conclusion was that large CpG islands depleted of activating motifs are bound by both PRC complexes in pluripotent stem cells [204,207]. In more recent studies bivalent domains were connected to different nucleosome remodeling complexes too (reviewed in [211]). There are numerous genetic variants of ES cell lines have been made in the past decades.…”