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Review
. 2015 Dec;16(12):1609-19.
doi: 10.15252/embr.201541011. Epub 2015 Nov 9.

Chromatin remodeling and bivalent histone modifications in embryonic stem cells

Arigela Harikumar  1 , Eran Meshorer  2
Affiliations
Review

Chromatin remodeling and bivalent histone modifications in embryonic stem cells

Arigela Harikumar et al. EMBO Rep. 2015 Dec.

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 ATP-dependent 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.

Keywords: chromatin; chromatin remodeling; embryonic stem cells; epigenetics; histone modifications.

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Figures

Figure 1
Figure 1. The bivalency concept
A bivalent gene, depicted as a boat (top left), is ready to go (sail up: H3K4me3) but is held in check (anchor: H3K27me3). Once the sail is down (top right), the gene is stably silenced (only H3K27me3), but if instead the anchor is lifted (bottom), the gene is promptly activated (only H3K4me3). [Correction added on 2 December 2015 after first online publication: “H4K4me3” has been corrected to “H3K4me3”.]
Figure 2
Figure 2. Main protein complexes catalyzing bivalent chromatin marks
Left: Protein complexes catalyzing H3K4 methylation (green flag). Right: The PRC2 complex catalyzing H3K27 methylation (red flag). Shown are only the main proteins and protein complexes catalyzing H3K4/H3K27 methylation. Less abundant subunits are not depicted. [Correction added on 2 December 2015 after first online publication: “H4K4” has been corrected to “H3K4”.]
Figure 3
Figure 3. The classical actions of chromatin remodeling proteins
Shown are different functional outcomes mediated by ATP‐dependent chromatin remodeling proteins, including nucleosome insertion (top left), nucleosome eviction (top right), dimer exchange (bottom left), and nucleosome sliding (bottom right). The chromatin remodeling proteins themselves are not depicted.
Figure 4
Figure 4. Chromatin remodeling complexes regulating bivalent nucleosomes
A single schematic bivalent nucleosome is shown (orange) marked with both H3K4me3 (green flag, left) and H3K27me3 (red flag, right). Chromatin remodeling complexes which were shown to regulate either or both marks are shown in green (esBAF), blue (NuRD), and mustard (INO80). Dotted arrows represent suggested regulation; dotted double lines represent potential interaction.
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