Activation of automethylated PRC2 by dimerization on chromatin

Sauer, P. V.; Pavlenko, E.; Cookis, T.; Zirden, L. C.; Renn, J.; Singhal, A.; Hunold, P.; Hoehne, M. N.; van Ray, O.; Haensel-Hertsch, R.; Sanbonmatsu, K. Y.; Nogales, E.; Poepsel, S.

doi:10.1101/2023.10.12.562141

bioRxiv · 10.1101/2023.10.12.562141

Activation of automethylated PRC2 by dimerization on chromatin

Sauer, P. V.·Pavlenko, E.·Cookis, T.·Zirden, L. C.·Renn, J.·Singhal, A.·Hunold, P.·Hoehne, M. N.·van Ray, O.·Haensel-Hertsch, R.·Sanbonmatsu, K. Y.·Nogales, E.·Poepsel, S.

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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.

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Sauer, P. V., Pavlenko, E., Cookis, T., Zirden, L. C., Renn, J., Singhal, A., Hunold, P., Hoehne, M. N., van Ray, O., Haensel-Hertsch, R., Sanbonmatsu, K. Y., Nogales, E., Poepsel, S.. 2023-10-13. Activation of automethylated PRC2 by dimerization on chromatin. https://doi.org/10.1101/2023.10.12.562141

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