Activation of automethylated PRC2 by dimerization on chromatin

Author:

Sauer Paul V.ORCID,Pavlenko EgorORCID,Cookis TrinityORCID,Zirden Linda C.ORCID,Renn Juliane,Singhal AnkushORCID,Hunold PascalORCID,Hoehne Michaela N.ORCID,van Ray Olivia,Hänsel-Hertsch RobertORCID,Sanbonmatsu Karissa Y.ORCID,Nogales EvaORCID,Poepsel SimonORCID

Abstract

SummaryPolycomb 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 allosterictrans-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.

Publisher

Cold Spring Harbor Laboratory

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