Activation of automethylated PRC2 by dimerization on chromatin

Abstract

Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator that trimethylates lysine 27 of histone 3 (H3K27me3) and is essential for embryonic development and cellular differentiation. H3K27me3 is associated with transcriptionally repressed chromatin and is established when PRC2 is allosterically activated upon methyl-lysine binding by the regulatory subunit EED. Automethylation of the catalytic subunit EZH2 stimulates its activity by an unknown mechanism. Here, we show that PRC2 forms a dimer on chromatin in which an inactive, automethylated PRC2 protomer is the allosteric activator of a second PRC2 that is poised to methylate H3 of a substrate nucleosome. Functional assays support our model of allosteric trans-autoactivation via EED, suggesting a novel mechanism mediating context-dependent activation of PRC2. Our work showcases the molecular mechanism of auto-modification coupled dimerization in the regulation of chromatin modifying complexes.

Multifunctional polymerization domains determine the onset of epigenetic silencing in Arabidopsis

“…Assembly size and order appear to be VEL-independent for VRN5, concurrent with VRN5-SYFP2 ΔVEL complementing the vrn5 mutant. Given the direct interaction between VRN5 and PRC2, we speculate that VEL-independent dimeric periodicity of VRN5 may be a result of the reported ability of PRC2 to undergo dimer formation (31)(32)(33). The lack of effect on VRN5 stoichiometry and FLC silencing in lines carrying VRN5 ΔVEL led us to question the properties of the VRN5 VEL domain.…”