Not just a writer: PRC2 as a chromatin reader

Abstract

PRC2 deposits the H3K27me3 repressive mark, which facilitates transcription repression of developmental genes. The decision of whether a particular gene is silenced at a given point during development is heavily dependent on the chromatin context. More than just a simple epigenetic writer, PRC2 employs several distinct chromatin reading capabilities to sense the local chromatin environment and modulate the H3K27me3 writer activity in a context-dependent manner. Here we discuss the complex interplay of PRC2 with the hallmarks of active and repressive chromatin, how it affects H3K27me3 deposition and how it guides transcriptional activity.

Keywords: DNA methylation; PRC2; chromatin reader; gene repression; histone modifications; polycomb repressive complex 2.

Figure 1.. The chromatin context guides PRC2 activity towards its appropriate target sites.

(A) Nucleosome occupancy can regulate PRC2 affinity for chromatin and PRC2 H3K27me3 methyltransferase activity. The binding preference of PRC2 for nucleosome-free linker DNA in vitro [41] and the anticorrelation of PRC2 binding and nucleosome density at CpG islands in cells [38] suggests highest affinity for regions of low nucleosome density. Increased nucleosome density, however, provides an increased density of the H3 substrate and, subsequently, the H3K27me3 effector. An intermediate nucleosome density may, therefore, allow for a good trade-off between substrate concentration and affinity and, subsequently, H3K27me3-induced allosteric activation [41,58]. (B) Hallmarks of active chromatin inhibit PRC2 activity. PRC2 is sequestered by RNA binding [41,68,79]. Free DNA at promoter regions is occupied by transcription factors and the histone methyltransferase activity of PRC2 is inhibited by the H3K36me3 [25,26] and H3K4me3 histone modifications [24,25], histone variant H3.3 [73] and RNA [78,80–83]. (C) Positive feedback loops auto-amplify H3K27me3 domain formation. H3K27me3 allosterically activates PRC2 [8–10]. H2A/H3.1 nucleosomes [73] and H2AK119-ubiquitinated nucleosomes [19–24] are preferred substrates for PRC2.