Activation of automethylated PRC2 by dimerization on chromatin.

PRC2 chromatin cryo-EM development epigenetics gene regulation histone methyltransferase trans-activation

Journal

Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571

Informations de publication

Date de publication:
13 Sep 2024
Historique:
received: 13 09 2023
revised: 31 05 2024
accepted: 21 08 2024
medline: 21 9 2024
pubmed: 21 9 2024
entrez: 20 9 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.molcel.2024.08.025 PMID: 39303719
pubmed: 39303719
pii: S1097-2765(24)00702-0
doi: 10.1016/j.molcel.2024.08.025
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Paul V Sauer (PV)

California Institute for Quantitative Biology (QB3), University of California, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA.

Egor Pavlenko (E)

Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, 50931 Cologne, Germany.

Trinity Cookis (T)

Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.

Linda C Zirden (LC)

Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, 50931 Cologne, Germany.

Juliane Renn (J)

Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, 50931 Cologne, Germany.

Ankush Singhal (A)

Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.

Pascal Hunold (P)

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.

Michaela N Hoehne-Wiechmann (MN)

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.

Olivia van Ray (O)

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.

Farnusch Kaschani (F)

Department of Chemical Biology, University of Duisburg-Essen, Center for Medical Biotechnology (ZMB), Faculty of Biology, Essen, Germany.

Markus Kaiser (M)

Department of Chemical Biology, University of Duisburg-Essen, Center for Medical Biotechnology (ZMB), Faculty of Biology, Essen, Germany.

Robert Hänsel-Hertsch (R)

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.

Karissa Y Sanbonmatsu (KY)

Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.

Eva Nogales (E)

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.

Simon Poepsel (S)

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.

Classifications MeSH