期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 44, 页码 27354-27364出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2006076117
关键词
oncohistones; H3.3 G34 mutations; PRC2; NSD1/2; SETD2
资金
- NIH [P01CA196539, R00CA212257]
- Greater Milwaukee Foundation
- RIDE Foundation for Cancer Research
- Sidney Kimmel Foundation (Kimmel Scholar Award)
- Carbone Cancer Center [P30CA014520]
- Leukemia and Lymphoma Society
- Genome Canada
- Genome Quebec
- Institute for Cancer Research of the Canadian Institutes for Health Research, McGill University
- Montreal Children's Hospital Foundation
- Damon Runyon Cancer Research Foundation [DFS-28-18]
- Pew-Stewart Scholar Award for Cancer Research
- American Association for Cancer Research Gertrude B. Elion Cancer Research Award
- Chercheur Clinician Senior Award
- Research Institute of the McGill University Health Centre Histopathology Platform
- [DP2OD007447]
- [R01GM110174]
- [T32GM008275]
- [TL1TR001880]
- [T32GM007739]
- [F30CA224971]
- NATIONAL CANCER INSTITUTE [P01CA196539] Funding Source: NIH RePORTER
A high percentage of pediatric gliomas and bone tumors reportedly harbor missense mutations at glycine 34 in genes encoding histone variant H3.3. We find that these H3.3 G34 mutations directly alter the enhancer chromatin landscape of mesenchymal stem cells by impeding methylation at lysine 36 on histone H3 (H3K36) by SETD2, but not by the NSD1/2 enzymes. The reduction of H3K36 methylation by G34 mutations promotes an aberrant gain of PRC2-mediated H3K27me2/3 and loss of H3K27ac at active enhancers containing SETD2 activity. This altered histone modification profile promotes a unique gene expression profile that supports enhanced tumor development in vivo. Our findings are mirrored in G34W-containing giant cell tumors of bone where patient-derived stromal cells exhibit gene expression profiles associated with early osteoblastic differentiation. Overall, we demonstrate that H3.3 G34 oncohistones selectively promote PRC2 activity by interfering with SETD2-mediated H3K36 methylation. We propose that PRC2-mediated silencing of enhancers involved in cell differentiation represents a potential mechanism by which H3.3 G34 mutations drive these tumors.
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