Activation of automethylated PRC2 by dimerization on chromatin.
| Title: | Activation of automethylated PRC2 by dimerization on chromatin. |
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| Authors: | Sauer PV; California Institute for Quantitative Biology (QB3), University of California, Berkeley, California 94720, USA.; Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA.; Pavlenko E; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, Germany.; Cookis T; Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.; Zirden LC; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, Germany.; Renn J; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, Germany.; Singhal A; Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory.; Hunold P; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Hoehne MN; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; van Ray O; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, Germany.; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.; Hänsel-Hertsch R; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of 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, Germany.; Sanbonmatsu KY; Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory.; Nogales E; California Institute for Quantitative Biology (QB3), University of California, Berkeley, California 94720, USA.; Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA.; Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.; Molecular Biophysics and Integrative Bio-Imaging Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.; Poepsel S; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, Germany.; Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Germany. |
| Source: | BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 13. Date of Electronic Publication: 2023 Oct 13. |
| Publication Type: | Preprint; Journal Article |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| 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. |
| Competing Interests: | Competing interests The authors declare no competing interests. |
| Comments: | Update in: Mol Cell. 2024 Oct 17;84(20):3885-3898.e8. doi: 10.1016/j.molcel.2024.08.025.. (PMID: 39303719) |
| Grant Information: | R01 GM129325 United States GM NIGMS NIH HHS; R35 GM127018 United States GM NIGMS NIH HHS |
| Contributed Indexing: | Keywords: chromatin; cryo-EM; development; epigenetics; gene regulation |
| Entry Date(s): | Date Created: 20231024 Latest Revision: 20241018 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10592840 |
| DOI: | 10.1101/2023.10.12.562141 |
| PMID: | 37873121 |
| Database: | MEDLINE |
Preprint; Journal Article