دورية أكاديمية
أعرض في EDS

Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation.

التفاصيل البيبلوغرافية
العنوان: Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation.
المؤلفون: Nacev BA; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA. ben46@pitt.edu.; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA. ben46@pitt.edu.; UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA. ben46@pitt.edu., Dabas Y; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, 10065, USA., Paul MR; Bioinformatics Resource Center, The Rockefeller University, New York, NY, 10065, USA., Pacheco C; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, 10065, USA., Mitchener M; Department of Chemistry, Princeton University, Princeton, NJ, 08544, USA., Perez Y; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Fang Y; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, 10065, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Soshnev AA; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, 10065, USA.; Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio, San Antonio, TX, 78249, USA., Barrows D; Bioinformatics Resource Center, The Rockefeller University, New York, NY, 10065, USA., Carroll T; Bioinformatics Resource Center, The Rockefeller University, New York, NY, 10065, USA., Socci ND; Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., St Jean SC; Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Tiwari S; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.; UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA., Gruss MJ; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.; UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA., Monette S; Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Tap WD; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Garcia BA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, 63110, USA., Muir T; Department of Chemistry, Princeton University, Princeton, NJ, 08544, USA., Allis CD; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, 10065, USA.
المصدر: Nature communications [Nat Commun] 2024 Jun 17; Vol. 15 (1), pp. 5155. Date of Electronic Publication: 2024 Jun 17.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Histones*/metabolism , Histones*/genetics , Cell Differentiation*/genetics , Arginine*/metabolism , Polycomb Repressive Complex 2*/metabolism , Polycomb Repressive Complex 2*/genetics , Neoplasms*/genetics , Neoplasms*/metabolism , Neoplasms*/pathology , Mutation*, Animals ; Humans ; Mice ; Chromatin/metabolism ; Epigenesis, Genetic ; Mesenchymal Stem Cells/metabolism ; Cell Line, Tumor
مستخلص: Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants is exclusively observed on the minor fraction of histone tails harboring the mutations, the same mutants recurrently disrupt broad H3K27me3 domains in the chromatin context, including near developmentally regulated promoters. H3K27me3 loss leads to de-repression of differentiation pathways, with concordant effects between H3R2 and H3R26 mutants despite different proximity to the PRC2 substrate, H3K27. Functionally, H3R26C-expressing mesenchymal progenitor cells and murine embryonic stem cell-derived teratomas demonstrate impaired differentiation. Collectively, these data show that cancer-associated H3 N-terminal arginine mutations reduce PRC2 activity and disrupt chromatin-dependent developmental functions, a cancer-relevant phenotype.
(© 2024. The Author(s).)
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معلومات مُعتمدة: R01 HD106051 United States HD NICHD NIH HHS; R01 CA234561 United States CA NCI NIH HHS; GM131632 U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS); HD106051 U.S. Department of Health & Human Services | National Institutes of Health (NIH); R01 AI118891 United States AI NIAID NIH HHS; P30CA047904 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI); R01CA234561 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI); T32 GM071339 United States GM NIGMS NIH HHS; K08CA245212 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI); P30 CA047904 United States CA NCI NIH HHS; P01CA196539 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI); P01 CA196539 United States CA NCI NIH HHS; P30CA008748 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI); P30 CA008748 United States CA NCI NIH HHS; 5T32GM071339-13 U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS); CHE-2127882 National Science Foundation (NSF); K08 CA245212 United States CA NCI NIH HHS; F32 GM131632 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (Histones)
94ZLA3W45F (Arginine)
EC 2.1.1.43 (Polycomb Repressive Complex 2)
0 (Chromatin)
تواريخ الأحداث: Date Created: 20240617 Date Completed: 20240617 Latest Revision: 20240717
رمز التحديث: 20240717
مُعرف محوري في PubMed: PMC11183192
DOI: 10.1038/s41467-024-49486-5
PMID: 38886411
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-024-49486-5