Journal
SCIENCE
Volume 352, Issue 6287, Pages 844-849Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aac7272
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Funding
- Rockefeller University
- Wisconsin Institute for Discovery
- Greater Milwaukee Foundation
- Starr Cancer Consortium [SCC I6-A614]
- Sidney Kimmel Foundation
- NIH [P01CA196539, DP2OD007447, R01GM110174, DP2CA174499, K08CA151660, K08CA181475]
- NIH (Cancer Center Support grant) [P30CA008748]
- Genome Canada
- Genome Quebec
- Institute for Cancer Research of the Canadian Institutes for Health Research (CIHR)
- McGill University
- Montreal Children's Hospital Foundation
- Damon Runyon Cancer Research Foundation [DRG-2195-14]
- Chercheur Clinician Senior Award
- Boehringer Ingelheim Fonds Predoctoral fellowship
- T.D Trust/Montreal Children's Hospital Foundation
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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.
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