Activation of automethylated PRC2 by dimerization on chromatin
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.
Authors
- Trinity Cookis (ORCID: https://orcid.org/0000-0002-5145-7508)
- Robert Hänsel‐Hertsch (ORCID: https://orcid.org/0000-0002-2835-4471)
- Olivia van Ray (ORCID: https://orcid.org/0000-0002-1449-0018)
- Markus Kaiser (ORCID: https://orcid.org/0000-0002-6540-8520)
- Karissa Y. Sanbonmatsu (ORCID: https://orcid.org/0000-0002-7965-7392)
- Eva Nogales (ORCID: https://orcid.org/0000-0001-9816-3681)
- Simon Poepsel (ORCID: https://orcid.org/0000-0002-8304-4062)
- Egor Pavlenko (ORCID: https://orcid.org/0000-0003-0293-052X)
- Ankush Singhal (ORCID: https://orcid.org/0000-0003-2949-6962)
- Farnusch Kaschani (ORCID: https://orcid.org/0000-0001-6572-3232)
- Linda C. Zirden (ORCID: https://orcid.org/0000-0003-2635-757X)
- Paul Sauer (ORCID: https://orcid.org/0000-0001-7204-5863)
- Pascal Hunold (ORCID: https://orcid.org/0000-0002-7087-5908)
- Michaela Nicole Hoehne‐Wiechmann
- Juliane Renn
Institutions
- Los Alamos National Laboratory (US)
- University Hospital Cologne (DE)
- University of Duisburg-Essen (DE)
- University of California, Berkeley (US)
Publication Details
- Journal
- Molecular Cell
- Published
- 2024-09-19
- DOI
- https://doi.org/10.1016/j.molcel.2024.08.025
- Citations
- 8
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- National Science Foundation
- Deutsche Forschungsgemeinschaft
- Universität zu Köln
- Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen
- National Institutes of Health
- University of California, San Francisco
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases
- Los Alamos National Laboratory