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. |
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| Authors: | Cookis T; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.; Lydecker A; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.; Sauer P; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA 94720.; Howard Hughes Medical Institute, University of California, Berkeley, CA 94720.; Kasinath V; Department of Biochemistry, University of Colorado, Boulder, CO 80303.; Nogales E; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA 94720.; Molecular Biophysics and Integrative Bio-Imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.; Howard Hughes Medical Institute, University of California, Berkeley, CA 94720. |
| Source: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 10. Date of Electronic Publication: 2024 Feb 10. |
| 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 essential for embryonic development and maintenance of cell identity that trimethylates histone H3 at lysine 27 (H3K27me3) leading to gene silencing. PRC2 is regulated by association with protein cofactors and crosstalk with histone posttranslational modifications. Trimethylated histone H3 K4 (H3K4me3) and K36 (H3K36me3) localize to sites of active transcription where H3K27me3 is absent and inhibit PRC2 activity through unknown mechanisms. Using cryo-electron microscopy we reveal that histone H3 tails modified with H3K36me3 engage poorly with the PRC2 active site and preclude its effective interaction with chromatin, while the H3K4me3 modification binds to the allosteric site in the EED subunit, acting as an antagonist that competes with allosteric activators required for the spreading of the H3K27me3 repressive mark. Thus, the location along the H3 tail of the H3K4me3 and H3K36me3 modifications allow them to target two essential requirements for efficient trimethylation of histone H3K27. We further show that the JARID2 cofactor modulates PRC2 activity in the presence of these histone modifications. |
| Competing Interests: | Competing Interest Statement: The authors declare no competing interests. |
| Comments: | Update in: Nat Struct Mol Biol. 2025 Feb;32(2):393-404. doi: 10.1038/s41594-024-01452-x.. (PMID: 39774834) |
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| 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; R35 GM155426 United States GM NIGMS NIH HHS; R00 GM132544 United States GM NIGMS NIH HHS |
| Contributed Indexing: | Keywords: Polycomb; allostery; antagonist; chromatin; cryo-EM; epigenetics; histone modifications |
| Entry Date(s): | Date Created: 20240219 Latest Revision: 20250202 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10871338 |
| DOI: | 10.1101/2024.02.09.579730 |
| PMID: | 38370759 |
| Database: | MEDLINE |
Preprint; Journal Article