The Polycomb complex PRC2 and its mark in life

Abstract

Polycomb group proteins maintain the gene-expression pattern of different cells that is set during early development by regulating chromatin structure. In mammals, two main Polycomb group complexes exist - Polycomb repressive complex 1 (PRC1) and 2 (PRC2). PRC1 compacts chromatin and catalyses the monoubiquitylation of histone H2A. PRC2 also contributes to chromatin compaction, and catalyses the methylation of histone H3 at lysine 27. PRC2 is involved in various biological processes, including differentiation, maintaining cell identity and proliferation, and stem-cell plasticity. Recent studies of PRC2 have expanded our perspectives on its function and regulation, and uncovered a role for non-coding RNA in the recruitment of PRC2 to target genes.

Figure 1

Schematic representation of Polycomb complex PRC1/2. Left) Diagrams representing the composition of PRC2 and PRC1 are shown. In the case of PRC1, the left diagrams correspond to the classical PRC1 complexes, while the right one corresponds to the so-called PRC1-like complexes. Due to their homology with Drosophila Psc protein, we assumed that Bmi-1-, Mel18- and NSPC1-containing PRC1 complex could compact chromatin. The CBXs “pocket” shape represent the chromodomain that specifically recognized H3K9/27me3. HPH1/2/3 are the abbreviation for Human Polyhomeotic Homolog 1/2/3. X, Y and Z represent various proteins such as SCMH1/2, FBXL10, E2F6, JARID1d that could contribute to the formation of PRC1-like complexes whose exact composition is still enigmatic. B) Characterized domains with potential functions are indicated for each PRC2 component. Note that domains based on evolutionary conservation are underscored below. For Ezh2, the numbers indicate the percent homology between mouse and Drosophila homologs.

Figure 2

Chromatin properties at PRC2 target genes in ES cells and differentiated cells. Schematic representation of chromatin at PcG target genes as a function of ES cell differentiation. In ES cells, most PcG targets are methylated on both H3K4 and H3K27 and colocalize with the histone variant H2Az. During differentiation, H2Az is removed, and some bivalent domains are resolved. For example, genes that are actively transcribed lose H3K27me3. A significant proportion of PcG targets that retain H3K27me3 but lose H3K4me3 are targeted by other silencing pathways such as DNA methylation or H3K9 trimethylation.

Figure 3

Multiple interactions of PRC2 with chromatin. Schematic representation of PRC2 holoenzyme at chromatin. Putative interactions with either DNA or histones that could explain PRC2 recruitment are highlighted.

Figure 4

PRC2 mediated regulation of pluripotency and differentiation. A) Comparison of expression levels of pluripotency factors and factors that induce cell commitment during ES cell differentiation in wild type and PRC2 impaired ES cells. B) Consequences to the outcome of cell differentiation upon PRC2 inactivation.