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-Wiechmann; Olivia van Ray; Farnusch Kaschani; Markus Kaiser; Robert Hänsel-Hertsch; Karissa Y Sanbonmatsu; Eva Nogales; Simon Poepsel

doi:10.1016/j.molcel.2024.08.025

Activation of automethylated PRC2 by dimerization on chromatin

Mol Cell. 2024 Oct 17;84(20):3885-3898.e8. doi: 10.1016/j.molcel.2024.08.025. Epub 2024 Sep 19.

Authors

Affiliations

¹ California Institute for Quantitative Biology (QB3), University of California, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA.
² Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, 50931 Cologne, Germany.
³ Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
⁴ Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
⁵ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, 50931 Cologne, Germany; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
⁶ Department of Chemical Biology, University of Duisburg-Essen, Center for Medical Biotechnology (ZMB), Faculty of Biology, Essen, Germany.
⁷ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, 50931 Cologne, Germany; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Institute of Human Genetics, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
⁸ California Institute for Quantitative Biology (QB3), University of California, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA; Molecular Biophysics and Integrative Bio-Imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address: enogales@lbl.gov.
⁹ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. Electronic address: spoepsel@uni-koeln.de.

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 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.

Keywords: PRC2; chromatin; cryo-EM; development; epigenetics; gene regulation; histone methyltransferase; trans-activation.

MeSH terms

Allosteric Regulation
Chromatin* / genetics
Chromatin* / metabolism
Enhancer of Zeste Homolog 2 Protein* / genetics
Enhancer of Zeste Homolog 2 Protein* / metabolism
HEK293 Cells
Histones* / genetics
Histones* / metabolism
Humans
Methylation
Nucleosomes / genetics
Nucleosomes / metabolism
Polycomb Repressive Complex 2* / genetics
Polycomb Repressive Complex 2* / metabolism
Protein Binding
Protein Multimerization*

Substances

Polycomb Repressive Complex 2
Chromatin
Histones
Enhancer of Zeste Homolog 2 Protein
EZH2 protein, human
Nucleosomes
EED protein, human

Abstract

MeSH terms

Substances

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