PRC2 functions in development and congenital disorders

Abstract

Polycomb repressive complex 2 (PRC2) is a conserved chromatin regulator that is responsible for the methylation of histone H3 lysine 27 (H3K27). PRC2 is essential for normal development and its loss of function thus results in a range of developmental phenotypes. Here, we review the latest advances in our understanding of mammalian PRC2 activity and present an updated summary of the phenotypes associated with its loss of function in mice. We then discuss recent studies that have highlighted regulatory interplay between the modifications laid down by PRC2 and other chromatin modifiers, including NSD1 and DNMT3A. Finally, we propose a model in which the dysregulation of these modifications at intergenic regions is a shared molecular feature of genetically distinct but highly phenotypically similar overgrowth syndromes in humans.

Keywords: DNMT3A; NSD1; PRC2; Sotos syndrome; Tatton-Brown–Rahman syndrome; Weaver syndrome.

Fig. 1.

Polycomb repressive complex 2 assembles into two subcomplexes. Schematic of the subunits of mammalian Polycomb repressive complex 2 (PRC2), including both core and accessory subunits. The composition of the PRC2.1 and PRC2.2 subcomplexes are also depicted. Note that PALI1 and EPOP are mutually exclusive members of PRC2.1, whereas RBBP4/7 associates with both PRC2.1 and PRC2.2. EZHIP has also been reported to interact with both PRC2.1 and PRC2.2 but is expressed in a limited range of cell types. Paralogous subunits and alternative protein names are listed where applicable. Contacts shown between subunits are merely schematic and are not intended to reflect actual physical interactions.

Fig. 2.

The crosstalk between PRC2, NSD1 and DNMT3A on chromatin. (A) Antagonistic interplay between NSD1-mediated H3K36me2, DNMT3A-mediated DNA methylation and PRC2-mediated H3K27me3 around Polycomb-bound CpG islands. Both DNA methylation and H3K36me2 are reported to antagonise the accumulation of PRC2-mediated H3K27me3. H3K27me3 allosterically activates PRC2. (B) Co-existence of PRC2-mediated H3K27me2, NSD1-mediated H3K36me2 and DNMT3A-mediated DNA methylation at intergenic chromatin. The crosstalk between these different chromatin regulators is illustrated by the ability of both DNMT3A and EZH2 to read the methylation status of H3K36.