Activation of automethylated PRC2 by dimerization on chromatin.
| Title: | Activation of automethylated PRC2 by dimerization on chromatin. |
|---|---|
| Authors: | 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.; Pavlenko E; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, 50931 Cologne, Germany.; Cookis T; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.; Zirden LC; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, 50931 Cologne, Germany.; Renn J; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital, University of Cologne, 50931 Cologne, Germany.; Singhal A; Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.; 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.; 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.; 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.; Kaschani F; Department of Chemical Biology, University of Duisburg-Essen, Center for Medical Biotechnology (ZMB), Faculty of Biology, Essen, Germany.; Kaiser M; Department of Chemical Biology, University of Duisburg-Essen, Center for Medical Biotechnology (ZMB), Faculty of Biology, Essen, Germany.; 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.; Sanbonmatsu KY; Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.; 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.; 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. |
| Source: | Molecular cell [Mol Cell] 2024 Oct 17; Vol. 84 (20), pp. 3885-3898.e8. Date of Electronic Publication: 2024 Sep 19. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Cell Press Country of Publication: United States NLM ID: 9802571 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4164 (Electronic) Linking ISSN: 10972765 NLM ISO Abbreviation: Mol Cell Subsets: MEDLINE |
| Imprint Name(s): | Publication: Cambridge Ma : Cell Press; Original Publication: Cambridge, Mass. : Cell Press, c1997- |
| MeSH Terms: | Polycomb Repressive Complex 2*/metabolism ; Polycomb Repressive Complex 2*/genetics ; Chromatin*/metabolism ; Chromatin*/genetics ; Histones*/metabolism ; Histones*/genetics ; Enhancer of Zeste Homolog 2 Protein*/metabolism ; Enhancer of Zeste Homolog 2 Protein*/genetics ; Protein Multimerization*; Nucleosomes/metabolism ; Nucleosomes/genetics ; Humans ; Methylation ; Allosteric Regulation ; HEK293 Cells ; Protein Binding |
| 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.; (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of interests The authors declare no competing interests. |
| Comments: | Update of: bioRxiv. 2023 Oct 13:2023.10.12.562141. doi: 10.1101/2023.10.12.562141.. (PMID: 37873121) |
| References: | Genome Biol. 2014;15(12):550. (PMID: 25516281); Nat Commun. 2019 Apr 11;10(1):1679. (PMID: 30976011); Methods Enzymol. 2017;592:1-26. (PMID: 28668116); Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517); Elife. 2018 Nov 09;7:. (PMID: 30412051); J Mol Biol. 1998 Feb 13;276(1):19-42. (PMID: 9514715); Nat Struct Mol Biol. 2018 Feb;25(2):154-162. (PMID: 29379173); Mol Cell Biol. 2007 May;27(10):3769-79. (PMID: 17339329); Bioinformatics. 2015 Jan 15;31(2):166-9. (PMID: 25260700); Nucleic Acids Res. 2016 Jan 4;44(D1):D447-56. (PMID: 26527722); Nat Methods. 2012 Sep;9(9):853-4. (PMID: 22842542); J Chem Theory Comput. 2008 Mar;4(3):435-47. (PMID: 26620784); Mol Cell. 2007 Aug 17;27(4):596-608. (PMID: 17707231); PLoS One. 2017 Oct 26;12(10):e0185056. (PMID: 29073143); Mol Cell. 2015 Mar 5;57(5):769-783. (PMID: 25620564); J Struct Biol. 2007 Jan;157(1):38-46. (PMID: 16859925); Mol Cell. 2020 Feb 20;77(4):840-856.e5. (PMID: 31883952); Genes Dev. 2019 Oct 1;33(19-20):1416-1427. (PMID: 31488576); J Struct Biol. 2015 Nov;192(2):216-21. (PMID: 26278980); Nat Methods. 2017 Mar;14(3):290-296. (PMID: 28165473); J Med Chem. 2022 Apr 14;65(7):5317-5333. (PMID: 35352560); Biophys J. 2007 Jun 1;92(11):3817-29. (PMID: 17351000); J Struct Biol. 2017 Dec;200(3):307-313. (PMID: 28259651); Methods Enzymol. 2004;375:23-44. (PMID: 14870657); J Chem Theory Comput. 2011 Sep 13;7(9):2886-2902. (PMID: 21921995); Biochemistry. 2019 Feb 5;58(5):346-354. (PMID: 30451485); Nature. 2018 Oct;562(7728):538-544. (PMID: 30323286); Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20980-5. (PMID: 21078963); J Mol Biol. 2003 Oct 31;333(4):721-45. (PMID: 14568533); Elife. 2020 Nov 19;9:. (PMID: 33211010); Science. 2015 Oct 16;350(6258):aac4383. (PMID: 26472914); Nature. 2021 Jan;589(7841):293-298. (PMID: 33299182); Protein Sci. 2021 Jan;30(1):70-82. (PMID: 32881101); Mol Cell. 2017 May 4;66(3):384-397.e8. (PMID: 28475873); Mol Cell Proteomics. 2005 Dec;4(12):2010-21. (PMID: 16249172); Science. 2023 Sep 22;381(6664):1331-1337. (PMID: 37733873); Nat Protoc. 2007;2(8):1896-906. (PMID: 17703201); J Vis Exp. 2023 Dec 29;(202):. (PMID: 38224121); Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501. (PMID: 20383002); Nature. 2009 Oct 8;461(7265):762-7. (PMID: 19767730); Genes Dev. 2019 Oct 1;33(19-20):1428-1440. (PMID: 31488577); Biophys J. 2012 Apr 18;102(8):1926-33. (PMID: 22768949); Nat Commun. 2016 Apr 28;7:11316. (PMID: 27121947); Biochem Soc Trans. 2021 Jun 30;49(3):1159-1170. (PMID: 34060617); Cell. 2002 May 3;109(3):275-82. (PMID: 12015977); Science. 2021 Jan 22;371(6527):. (PMID: 33479123); Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21. (PMID: 20124702); BMC Biotechnol. 2020 May 12;20(1):26. (PMID: 32398045); Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886); Mol Cell. 2004 Sep 10;15(5):661-75. (PMID: 15350212); Acta Crystallogr D Struct Biol. 2018 Jun 1;74(Pt 6):519-530. (PMID: 29872003); Nat Methods. 2023 Jun;20(6):860-870. (PMID: 37169929); Mol Cell. 2014 Jan 23;53(2):290-300. (PMID: 24374312); Sci Adv. 2021 Jun 25;7(26):. (PMID: 34172444); Nat Methods. 2017 Apr;14(4):331-332. (PMID: 28250466); Science. 2018 Feb 23;359(6378):940-944. (PMID: 29348366); Bioinformatics. 2009 Aug 15;25(16):2078-9. (PMID: 19505943); Mol Cell. 2018 Jun 21;70(6):1149-1162.e5. (PMID: 29932905); Nat Chem Biol. 2017 Apr;13(4):381-388. (PMID: 28135235); Nat Rev Mol Cell Biol. 2006 Sep;7(9):667-77. (PMID: 16921403); J Struct Biol. 2012 Oct;180(1):249-53. (PMID: 22584152); Nat Protoc. 2019 Jan;14(1):68-85. (PMID: 30464214); Nat Struct Mol Biol. 2004 Apr;11(4):308-15. (PMID: 15004546); Nat Commun. 2021 Jan 29;12(1):714. (PMID: 33514705) |
| Grant Information: | United States HHMI Howard Hughes Medical Institute; R01 GM129325 United States GM NIGMS NIH HHS; R35 GM127018 United States GM NIGMS NIH HHS |
| Contributed Indexing: | Keywords: PRC2; chromatin; cryo-EM; development; epigenetics; gene regulation; histone methyltransferase; trans-activation |
| Substance Nomenclature: | EC 2.1.1.43 (Polycomb Repressive Complex 2); 0 (Chromatin); 0 (Histones); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein); EC 2.1.1.43 (EZH2 protein, human); 0 (Nucleosomes); 0 (EED protein, human) |
| Entry Date(s): | Date Created: 20240920 Date Completed: 20241018 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11980035 |
| DOI: | 10.1016/j.molcel.2024.08.025 |
| PMID: | 39303719 |
| Database: | MEDLINE |
Journal Article