Structural basis for the inhibition of PRC2 by active transcription histone posttranslational modifications.
| Title: | Structural basis for the inhibition of PRC2 by active transcription histone posttranslational modifications. |
|---|---|
| Authors: | Cookis T; Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.; Lydecker A; Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.; Sauer P; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA.; Molecular Biophysics and Integrative Bio-Imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.; Kasinath V; Department of Biochemistry, University of Colorado, Boulder, CO, USA.; Nogales E; Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA. enogales@lbl.gov.; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA. enogales@lbl.gov.; Molecular Biophysics and Integrative Bio-Imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. enogales@lbl.gov.; Howard Hughes Medical Institute, University of California, Berkeley, CA, USA. enogales@lbl.gov. |
| Source: | Nature structural & molecular biology [Nat Struct Mol Biol] 2025 Feb; Vol. 32 (2), pp. 393-404. Date of Electronic Publication: 2025 Jan 07. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101186374 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1545-9985 (Electronic) Linking ISSN: 15459985 NLM ISO Abbreviation: Nat Struct Mol Biol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: New York : Nature Pub. Group, c2004- |
| MeSH Terms: | Polycomb Repressive Complex 2*/metabolism ; Polycomb Repressive Complex 2*/chemistry ; Polycomb Repressive Complex 2*/antagonists & inhibitors ; Histones*/metabolism ; Histones*/chemistry ; Protein Processing, Post-Translational*; Chromatin/metabolism ; Cryoelectron Microscopy ; Humans ; Methylation ; Models, Molecular ; Transcription, Genetic ; Protein Binding ; Animals |
| Abstract: | Polycomb repressive complex 2 (PRC2) trimethylates histone H3 on K27 (H3K27me3) leading to gene silencing that is essential for embryonic development and maintenance of cell identity. PRC2 is regulated by protein cofactors and their crosstalk with histone modifications. Trimethylated histone H3 on K4 (H3K4me3) and K36 (H3K36me3) localize to sites of active transcription and inhibit PRC2 activity through unknown mechanisms. Using cryo-electron microscopy, we reveal that histone H3 tails containing H3K36me3 engage poorly with PRC2 and preclude its effective interaction with chromatin, while H3K4me3 binds to the allosteric site in the EED subunit, acting as an antagonist that competes with activators required for spreading of the H3K27me3 repressive mark. Thus, the location of the H3K4me3 and H3K36me3 modifications along the H3 tail allows them to target two requirements for efficient trimethylation of H3K27 by PRC2. We further show that the JARID2 cofactor modulates PRC2 activity in the presence of these histone modifications.; (© 2025. The Author(s).) |
| Competing Interests: | Competing interests: The authors declare no competing interests. |
| Comments: | Update of: bioRxiv. 2024 Feb 10:2024.02.09.579730. doi: 10.1101/2024.02.09.579730.. (PMID: 38370759) |
| References: | Nat Commun. 2021 Jul 28;12(1):4592. (PMID: 34321472); Mol Cell. 2024 Oct 17;84(20):3885-3898.e8. (PMID: 39303719); Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19266-71. (PMID: 20974918); Nat Struct Mol Biol. 2012 Dec;19(12):1266-72. (PMID: 23142980); J Biol Chem. 2011 Nov 11;286(45):39457-65. (PMID: 21937433); Mol Cell Biol. 2006 Dec;26(24):9185-95. (PMID: 17030614); J Struct Biol. 2012 Dec;180(3):519-30. (PMID: 23000701); Mol Cell. 2011 May 6;42(3):330-41. (PMID: 21549310); Mol Cell. 2015 Mar 5;57(5):769-783. (PMID: 25620564); Mol Cell. 2014 Jan 9;53(1):49-62. (PMID: 24289921); Genes Dev. 2010 Feb 15;24(4):368-80. (PMID: 20123894); Genome Res. 2016 Jul;26(7):896-907. (PMID: 27197219); Science. 2012 Aug 24;337(6097):971-5. (PMID: 22923582); J Struct Biol. 2015 Nov;192(2):216-21. (PMID: 26278980); Mol Cell. 2018 May 3;70(3):422-434.e6. (PMID: 29681499); Science. 2002 Nov 1;298(5595):1039-43. (PMID: 12351676); Nat Struct Mol Biol. 2017 Dec;24(12):1039-1047. (PMID: 29058710); RNA Biol. 2019 Feb;16(2):176-184. (PMID: 30608221); Cell Rep. 2012 Nov 29;2(5):1169-77. (PMID: 23103171); J Biol Chem. 2005 May 6;280(18):17732-6. (PMID: 15760899); Biochim Biophys Acta Gene Regul Mech. 2020 Aug;1863(8):194567. (PMID: 32360393); J Struct Biol. 2016 Aug;195(2):238-244. (PMID: 27320699); Nat Commun. 2016 Nov 28;7:13661. (PMID: 27892467); Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20980-5. (PMID: 21078963); Cell Rep. 2016 Oct 4;17(2):583-595. (PMID: 27705803); J Biol Chem. 2002 Dec 20;277(51):49383-8. (PMID: 12381723); Cell. 2013 Feb 28;152(5):1021-36. (PMID: 23452851); Elife. 2020 Nov 19;9:. (PMID: 33211010); Nat Biotechnol. 2010 Aug;28(8):817-25. (PMID: 20657582); Nat Struct Mol Biol. 2017 Dec;24(12):1028-1038. (PMID: 29058709); Science. 2015 Oct 16;350(6258):aac4383. (PMID: 26472914); Protein Sci. 2021 Jan;30(1):70-82. (PMID: 32881101); Nature. 2011 Mar 24;471(7339):480-5. (PMID: 21179089); Science. 2023 Sep 22;381(6664):1331-1337. (PMID: 37733873); J Biol Chem. 2011 Mar 11;286(10):7983-7989. (PMID: 21239496); J Vis Exp. 2023 Dec 29;(202):. (PMID: 38224121); Nature. 2009 Oct 8;461(7265):762-7. (PMID: 19767730); Development. 2016 Aug 1;143(15):2716-23. (PMID: 27317809); Nat Struct Mol Biol. 2018 Mar;25(3):225-232. (PMID: 29483650); Nature. 2023 Mar;615(7951):339-348. (PMID: 36859550); Nat Commun. 2016 Apr 28;7:11316. (PMID: 27121947); Mol Cell. 2018 Apr 19;70(2):371-379.e5. (PMID: 29606589); Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32. (PMID: 15572765); Mol Cell. 2018 May 3;70(3):408-421.e8. (PMID: 29628311); Science. 2021 Jan 22;371(6527):. (PMID: 33479123); Acta Crystallogr D Biol Crystallogr. 2002 Nov;58(Pt 11):1948-54. (PMID: 12393927); Acta Crystallogr D Struct Biol. 2018 Jun 1;74(Pt 6):519-530. (PMID: 29872003); Wiley Interdiscip Rev Dev Biol. 2013 Sep-Oct;2(5):685-700. (PMID: 24014454); Cell. 2007 Oct 5;131(1):58-69. (PMID: 17884155); Nat Struct Mol Biol. 2018 Feb;25(2):154-162. (PMID: 29379173); Nature. 2010 Mar 11;464(7286):306-10. (PMID: 20075857); Mol Cell Biol. 2005 Apr;25(8):3305-16. (PMID: 15798214); Nat Cell Biol. 2004 Jan;6(1):73-7. (PMID: 14661024); Commun Biol. 2019 Jun 19;2:218. (PMID: 31240256); Nat Methods. 2017 Apr;14(4):331-332. (PMID: 28250466); Science. 2018 Feb 23;359(6378):940-944. (PMID: 29348366); Mol Cell. 2018 Jun 21;70(6):1149-1162.e5. (PMID: 29932905); Genes Dev. 2018 Jun 1;32(11-12):794-805. (PMID: 29891558); Cell. 2005 Jan 28;120(2):169-81. (PMID: 15680324); Cell. 2005 Aug 26;122(4):517-27. (PMID: 16122420); Nature. 2002 Sep 26;419(6905):407-11. (PMID: 12353038); Nat Commun. 2021 Jan 29;12(1):714. (PMID: 33514705); Nat Struct Mol Biol. 2014 Jun;21(6):569-71. (PMID: 24837194); Genes Dev. 2014 Sep 15;28(18):1983-8. (PMID: 25170018) |
| Grant Information: | R35 GM127018 United States GM NIGMS NIH HHS; T32 GM008295 United States GM NIGMS NIH HHS; U24 GM129541 United States GM NIGMS NIH HHS |
| Substance Nomenclature: | EC 2.1.1.43 (Polycomb Repressive Complex 2); 0 (Histones); 0 (Chromatin); 0 (histone H3 trimethyl Lys4) |
| Entry Date(s): | Date Created: 20250108 Date Completed: 20250430 Latest Revision: 20250520 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11832421 |
| DOI: | 10.1038/s41594-024-01452-x |
| PMID: | 39774834 |
| Database: | MEDLINE |
Journal Article