@article{f8c0dee7737d4a99ad81fc83849bf271,
title = "Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression",
abstract = "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.",
keywords = "H3.3 G34 mutations, NSD1/2, Oncohistones, PRC2, SETD2",
author = "Jain, {Siddhant U.} and Sima Khazaei and Marchione, {Dylan M.} and Lundgren, {Stefan M.} and Xiaoshi Wang and Weinberg, {Daniel N.} and Shriya Deshmukh and Nikoleta Juretic and Chao Lu and {David Allis}, C. and Garcia, {Benjamin A.} and Nada Jabado and Lewis, {Peter W.}",
note = "Funding Information: ACKNOWLEDGMENTS. This research was supported by funding from NIH P01CA196539 (to P.W.L., N. Jabado, C.D.A., and B.A.G.); the Greater Milwaukee Foundation (to P.W.L.), the RIDE Foundation for Cancer Research (to P.W.L.), the Sidney Kimmel Foundation (Kimmel Scholar Award to P.W.L.), and the Carbone Cancer Center (P30CA014520). P.W.L. is a Pew Scholar in the Biomedical Sciences. Innovator grant DP2OD007447, R01GM110174 and Robert Arceci Scholar Award from the Leukemia and Lymphoma Society (to B.A.G.). This work was performed within the context of the I-CHANGE consortium and supported by funding from Genome Canada, Genome Quebec, The Institute for Cancer Research of the Canadian Institutes for Health Research, McGill University, and the Montreal Children{\textquoteright}s Hospital Foundation. D.M.M. is supported by T32GM008275 and TL1TR001880. D.N.W. is supported by T32GM007739 and F30CA224971. C.L. acknowledges support from NIH (R00CA212257), Damon Runyon Cancer Research Foundation (DFS-28-18), Pew-Stewart Scholar Award for Cancer Research, and an American Association for Cancer Research Gertrude B. Elion Cancer Research Award. N. Jabado. is a member of the Penny Cole laboratory and the recipient of a Chercheur Clinician Senior Award. We thank Joseph Cesare for his help with mass spectrometry data analyses; Dr. Jason Karamchandani, pathologist at Department of Pathology, McGill University, and McGill University Health Center, who characterized the tumors from the xenograft study. All histological staining was performed with the support of the Research Institute of the McGill University Health Centre Histopathology Platform. Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = nov,
day = "3",
doi = "10.1073/pnas.2006076117",
language = "English",
volume = "117",
pages = "27354--27364",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "44",
}