Activation of automethylated PRC2 by dimerization on chromatin

Paul V Sauer; Egor Pavlenko; Trinity Cookis; Linda C Zirden; Juliane Renn; Ankush Singhal; Pascal Hunold; Michaela N Hoehne; Olivia van Ray; Robert Hänsel-Hertsch; Karissa Y Sanbonmatsu; Eva Nogales; Simon Poepsel

doi:10.1101/2023.10.12.562141

Activation of automethylated PRC2 by dimerization on chromatin

bioRxiv [Preprint]. 2023 Oct 13:2023.10.12.562141. doi: 10.1101/2023.10.12.562141.

Authors

Paul V Sauer^{1

2}, Egor Pavlenko³, Trinity Cookis⁴, Linda C Zirden³, Juliane Renn³, Ankush Singhal⁵, Pascal Hunold^{3

6}, Michaela N Hoehne^{3

6}, Olivia van Ray^{3

6}, Robert Hänsel-Hertsch^{3

6

7

8}, Karissa Y Sanbonmatsu⁵, Eva Nogales^{1

2

4

9}, Simon Poepsel^{3

8}

Affiliations

¹ California Institute for Quantitative Biology (QB3), University of California, Berkeley, California 94720, USA.
² Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA.
³ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, Germany.
⁴ Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
⁵ Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory.
⁶ Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
⁷ Institute of Human Genetics, University Hospital Cologne, 50931 Cologne, Germany.
⁸ Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Germany.
⁹ Molecular Biophysics and Integrative Bio-Imaging Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

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.

Keywords: chromatin; cryo-EM; development; epigenetics; gene regulation.

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Preprint

Abstract

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