Activation of automethylated PRC2 by dimerization on chromatin

作者：Paul Sauer, Egor Pavlenko, Trinity Cookis, Linda C. Zirden, Juliane Renn, Ankush Singhal, Pascal Hunold, Michaela Nicole Hoehne‐Wiechmann, Olivia van Ray, Farnusch Kaschani, Markus Kaiser, Robert Hänsel‐Hertsch, Karissa Y. Sanbonmatsu, Eva Nogales, Simon Poepsel · 发表于：Molecular Cell · 年份：2024 · DOI：10.1016/j.molcel.2024.08.025 · 被引用次数：11 · 研究领域：Epigenetics and DNA Methylation、DNA Repair Mechanisms、Cancer-related gene regulation

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 enhancer of zeste homolog 2 (EZH2) stimulates its activity by an unknown mechanism. Here, we show that human 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 previously unknown 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.