@article{72247d28831b408dac3e24de685acc23,
title = "Cancer: Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape",
abstract = "Several types of pediatric cancers reportedly contain high-frequency missense mutations in histone H3, yet the underlying oncogenic mechanism remains poorly characterized. Here we report that the H3 lysine 36-to-methionine (H3K36M) mutation impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma in vivo. H3K36M mutant nucleosomes inhibit the enzymatic activities of several H3K36 methyltransferases. Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient to phenocopy the H3K36M mutation. After the loss of H3K36 methylation, a genome-wide gain in H3K27 methylation leads to a redistribution of polycomb repressive complex 1 and de-repression of its target genes known to block mesenchymal differentiation. Our findings are mirrored in human undifferentiated sarcomas in which novel K36M/I mutations in H3.1 are identified.",
author = "Chao Lu and Jain, {Siddhant U.} and Dominik Hoelper and Denise Bechet and Molden, {Rosalynn C.} and Leili Ran and Devan Murphy and Sriram Venneti and Meera Hameed and Pawel, {Bruce R.} and Wunder, {Jay S.} and Dickson, {Brendan C.} and Lundgren, {Stefan M.} and Jani, {Krupa S.} and {De Jay}, Nicolas and Simon Papillon-Cavanagh and Andrulis, {Irene L.} and Sawyer, {Sarah L.} and David Grynspan and Turcotte, {Robert E.} and Javad Nadaf and Somayyeh Fahiminiyah and Muir, {Tom W.} and Jacek Majewski and Thompson, {Craig B.} and Ping Chi and Garcia, {Benjamin A.} and Allis, {C. David} and Nada Jabado and Lewis, {Peter W.}",
note = "Funding Information: This research was supported by funding from Rockefeller University (to C.D.A.), a startup provided by the Wisconsin Institute for Discovery (to P.W.L.), the Greater Milwaukee Foundation (to P.W.L), the Starr Cancer Consortium (grant SCC I6-A614 to C.D.A.), the Sidney Kimmel Foundation (Kimmel Scholar Award to P.C. and P.W.L.), and NIH grants (P01CA196539 to P.W.L., C.D.A., T.W.M., N.J., J.M., and B.A.G.; Innovator grant DP2OD007447 and R01GM110174 to B.A.G.; DP2CA174499 and K08CA151660 to P.C.; K08CA181475 to S.V.; and Cancer Center Support grant P30CA008748 to C.B.T.). 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 (CIHR), McGill University, and the Montreal Children's Hospital Foundation. C.L. is the Kandarian Family Fellow supported by the Damon Runyon Cancer Research Foundation (grant DRG-2195-14). N.J. is a member of the Penny Cole lab and the recipient of a Chercheur Clinician Senior Award. J.M. holds a Canada Research Chair (tier 2). D.H. is supported by a Boehringer Ingelheim Fonds Predoctoral fellowship. D.B. is supported by a studentship from the T.D Trust/Montreal Children's Hospital Foundation. C.B.T. is a founder of Agios Pharmaceuticals and a member of its scientific advisory board and also serves on the board of directors of Merck and Charles River Laboratories. R.E.T. is the president of the Quebec Orthopaedic Association. We thank the molecular cytology core facility of Memorial Sloan Kettering Cancer Center for technical help and EMD Millipore for H3.3K36M antibody generation. The sequencing data reported in this paper are deposited at the Gene Expression Omnibus database (accession number GSE69291).",
year = "2016",
month = may,
day = "13",
doi = "10.1126/science.aac7272",
language = "English (US)",
volume = "352",
pages = "844--849",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6287",
}