Cancer-associated histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation Journal Article

   

Authors:	Nacev, B. A.; Dabas, Y.; Paul, M. R.; Pacheco, C.; Mitchener, M.; Perez, Y.; Fang, Y.; Soshnev, A. A.; Barrows, D.; Carroll, T.; Socci, N. D.; St. Jean, S. C.; Tiwari, S.; Gruss, M. J.; Monette, S.; Tap, W. D.; Garcia, B. A.; Muir, T.; Allis, C. D.
Article Title:	Cancer-associated histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation
Abstract:	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. © The Author(s) 2024.
Keywords:	controlled study; protein expression; gene mutation; human cell; promoter region; genetics; mutation; nonhuman; neoplasm; neoplasms; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; gene expression; embryo; embryonic stem cell; animal experiment; animal model; protein; cell differentiation; pathology; enzyme activity; enzyme substrate; cell line, tumor; amino terminal sequence; histone; histone methyltransferase; chromatin; epigenesis, genetic; histone h3; gene repression; tumor cell line; mesenchymal stem cell; gene control; teratoma; genetic epigenesis; histones; arginine; differentiation; mesenchymal stem cells; germ layer; histone modification; polycomb repressive complex 2; cancer; humans; human; female; article; malignant neoplasm; induced response
Journal Title:	Nature Communications
Volume:	15
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2024-06-17
Start Page:	5155
Language:	English
DOI:	10.1038/s41467-024-49486-5
PUBMED:	38886411
PROVIDER:	scopus
PMCID:	PMC11183192
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85196213754&doi=10.1038%2fs41467-024-49486-5&partnerID=40&md5=2621c359ec1cf01b5c45ea56a69257c1
Notes:	Article -- Erratum issued, see DOI: 10.1038/s41467-024-53502-z -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/216933