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Review
. 2013 Mar 7;49(5):808-24.
doi: 10.1016/j.molcel.2013.02.013.

Occupying chromatin: Polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put

Jeffrey A Simon  1 , Robert E Kingston
Affiliations
Review

Occupying chromatin: Polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put

Jeffrey A Simon et al. Mol Cell. .

Abstract

Chromatin modification by Polycomb proteins provides an essential strategy for gene silencing in higher eukaryotes. Polycomb repressive complexes (PRCs) silence key developmental regulators and are centrally integrated in the transcriptional circuitry of stem cells. PRC2 trimethylates histone H3 on lysine 27 (H3K27me3), and PRC1-type complexes ubiquitylate histone H2A and compact polynucleosomes. How PRCs are deployed to select and silence genomic targets is the subject of intense investigation. We review advances on targeting, modulation, and functions of PRC1 and PRC2 and progress on defining the transcriptional steps they impact. Recent findings emphasize PRC1 targeting independent of H3K27me3, nonenzymatic PRC1-mediated compaction, and connections between PRCs and noncoding RNAs. Systematic analyses of Polycomb complexes and associated histone modifications during DNA replication and mitosis have also emerged. The stage is now set to reveal fundamental epigenetic mechanisms that determine how Polycomb target genes are silenced and how Polycomb silence is preserved through cell-cycle progression.

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Figures

Figure 1
Figure 1. Compositions and activities of PcG complexes
A) PRC2 family of complexes. Core subunits are in lavendar and arrows depict association of optional subunits. Dashed lines indicate alternative subunits derived from multiple gene copies or protein variants from a single gene. B) and C) PRC1 family of complexes. B) Canonical PRC1 with four core subunits including a PC homolog (CBX in mammals). C) and D) PRC1 variants that contain KDM2 and/or RYBP subunits. In human PRC1 complexes, assembly of RYBP and CBX subunits are mutually exclusive. See (Gao et al., 2012; Gearhart et al., 2006; Lagarou et al., 2008; Tavares et al., 2012) for detailed descriptions of PRC1 variants. Ubiquitylation occurs on H2A-K119 in mammals, corresponding to K118 in Drosophila. E) PHO-RC and F) PR-DUB from Drosophila. Human homologs of PHO (YY1), SFMBT, ASX and Calypso (BAP1) exist and mammalian complexes containing ASXL1/2 and BAP1 have been described (Dey et al., 2012). Mammalian complexes comparable to fly PHO-RC have not been characterized.
Figure 2
Figure 2. Optional subunits and chromatin features that modulate PRC2
A) Domain organizations of PCLs and JARID2. B) Features of the histone H3 tail that modulate PRC2 activity. Yellow circles denote trimethylation. PRC2 trimethylates K27; this activity is inhibited by K4me3 and K36me2/3 in cis (red bars) and is stimulated by K27me3 and H3 peptide 31-42 in trans (green arrows). C) Sites within SU(Z)12 and EED subunits (labeled “S”) mediate inhibition (red bars) or stimulation (green arrows) of PRC2 enzyme activity, presumably by impacting the SET domain active site (black arrows).
Figure 3
Figure 3. Mechanisms of repression by PRC1 family complexes
A) Ubiquitylation of histone H2A, normally by the PRC1 variant that includes a KDM2B/FBXL10-type subunit. It is not known how ubiquitylation impacts transcription, but inhibition has been proposed to occur after initiation. B) Compaction of the chromatin template by canonical PRC1 containing the PC/CBX and PH subunits. Compaction might occur over promoter regions, in gene bodies, or throughout the gene. C) PRC1 interacting with the general transcription factor TFIID and blocking association of the Mediator complex required for transcriptional activation.
Figure 4
Figure 4. Mechanisms of PcG maintenance during replication and mitosis
A) PRC1 is retained at the replication fork in S phase. One mechanism with biochemical support involves bridging between the PSC subunits of adjacent PRC1 complexes to maintain contact as the replication fork progresses through a region. B) The H3-K27me3 mark (red circles) binds the PRC2 complex and stimulates activity, creating a mechanism to maintain local K27me3 following replication and deposition of new nucleosomes. C) PRC1 components remain associated with mitotic chromatin at a subset of the locations bound during other stages of the cell cycle. This might help “seed” repopulation of sites by PRC1 upon G1 re-entry. Blue arrow denotes transcription start site of a resident gene.
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