Abstract
ABSTRACTPolycomb 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.
Highlights
Every multicellular organism begins life as a single cell that gives rise to the many functionally diverse cell types of the developing and adult organism
We describe recent molecular insights that are illuminating the regulatory interplay between the activities of Polycomb repressive complex 2 (PRC2), nuclear receptor-binding SET domain 1 (NSD1) and DNA (cytosine-5)methyltransferase 3A (DNMT3A) on chromatin
Imbalanced regulation of PRC2 at intergenic chromatin as a common feature of overgrowth syndromes Considering the convergence of PRC2-mediated H3K27me2, NSD1mediated H3K36me2 and DNMT3A-mediated DNA methylation at intergenic chromatin, we propose that an equilibrium exists between these modifications and that a shared molecular feature of the abovenamed developmental disorders may be disruptions to this balance, which shift the landscape of PRC2-mediated methylation (Fig. 2)
Summary
Every multicellular organism begins life as a single cell that gives rise to the many functionally diverse cell types of the developing and adult organism. Similar to Weaver syndrome, these conditions are marked by childhood overgrowth, dysmorphic facial features and learning disabilities (Okamoto et al, 2016; Tatton-Brown et al, 2005) In this Review, we discuss the latest advances in our knowledge of the molecular biology of PRC2 and present an updated summary of the developmental phenotypes associated with its loss of function in mice. PRC2 composition in mammals Mammalian PRC2 consists of three core subunits (Fig. 1): SUZ12, EED and either the EZH2 or EZH1 histone methyltransferase (HMT) (Laugesen et al, 2019; Yu et al, 2019) These core PRC2 proteins associate in a 1:1:1 stoichiometry and catalyse all mono-, di- and tri-methylation of histone H3 lysine 27 (H3K27) through the SET domain of the EZH1/2 subunit (Højfeldt et al, 2018; Smits et al, 2013).
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