Distinct Stimulatory Mechanisms Regulate the Catalytic Activity of Polycomb Repressive Complex 2

Abstract

© 2018 Elsevier Inc.The maintenance of gene expression patterns during metazoan development is achieved, in part, by the actions of polycomb repressive complex 2 (PRC2). PRC2 catalyzes mono-, di-, and trimethylation of histone H3 at lysine 27 (H3K27), with H3K27me2/3 being strongly associated with silenced genes. We demonstrate that EZH1 and EZH2, the two mutually exclusive catalytic subunits of PRC2, are differentially activated by various mechanisms. Whereas both PRC2-EZH1 and PRC2-EZH2 are able to catalyze mono- and dimethylation, only PRC2-EZH2 is strongly activated by allosteric modulators and specific chromatin substrates to catalyze trimethylation of H3K27 in mouse embryonic stem cells (mESCs). However, we also show that a PRC2-associated protein, AEBP2, can stimulate the activity of both complexes through a mechanism independent of and additive to allosteric activation. These results have strong implications regarding the cellular requirements for and the accompanying adjustments in PRC2 activity, given the differential expression of EZH1 and EZH2 upon cellular differentiation. Lee and Holder et al. provide mechanistic explanations of differential activities of PRC2-EZH1 and PRC2-EZH2 by nucleosome substrates, their response to allosteric activator, and cofactors. The interplay between these mechanisms impacts different levels of H3K27 methylation by the PRC2 complex and explains the regulation of PRC2 activity in development.