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TitleActivation of automethylated PRC2 by dimerization on chromatin.
Journal, issue, pagesMol Cell, Vol. 84, Issue 20, Page 3885-33898.e8, Year 2024
Publish dateOct 17, 2024
AuthorsPaul 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 /
PubMed AbstractPolycomb 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 ...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.
External linksMol Cell / PubMed:39303719
MethodsEM (single particle)
Resolution3.1 - 6.2 Å
Structure data

41110

8t9g

EMDB-41110, PDB-8t9g:
Automethylated PRC2 dimer bound to nucleosome
Method: EM (single particle) / Resolution: 6.2 Å

41141

8tas

EMDB-41141, PDB-8tas:
PRC2 monomer bound to nucleosome
Method: EM (single particle) / Resolution: 4.1 Å

41146

8tb9

EMDB-41146, PDB-8tb9:
PRC2-J119-450 monomer bound to H1-nucleosome
Method: EM (single particle) / Resolution: 4.0 Å

EMDB-41147: H1-nucleosome (chromatosome)
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-SAH:
S-ADENOSYL-L-HOMOCYSTEINE

Source
  • homo sapiens (human)
  • xenopus laevis (African clawed frog)
  • synthetic construct (others)
KeywordsGENE REGULATION / Histone methyl transferase / gene repression / epigenetics / chromatin

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