Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape

• Published in: Science (American Association for the Advancement of Science) Vol. 352; no. 6287; pp. 844 - 849
• Main Authors: Lu, Chao, Jain, Siddhant U., Hoelper, Dominik, Bechet, Denise, Molden, Rosalynn C., Ran, Leili, Murphy, Devan, Venneti, Sriram, Hameed, Meera, Pawel, Bruce R., Wunder, Jay S., Dickson, Brendan C., Lundgren, Stefan M., Jani, Krupa S., De Jay, Nicolas, Papillon-Cavanagh, Simon, Andrulis, Irene L., Sawyer, Sarah L., Grynspan, David, Turcotte, Robert E., Nadaf, Javad, Fahiminiyah, Somayyeh, Muir, Tom W., Majewski, Jacek, Thompson, Craig B., Chi, Ping, Garcia, Benjamin A., Allis, C. David, Jabado, Nada, Lewis, Peter W.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 13-05-2016; The American Association for the Advancement of Science
• Subjects: Amino acids; Animals; Bone Neoplasms - genetics; Bone Neoplasms - pathology; Cancer; Carcinogenesis - genetics; Carcinogenesis - pathology; Child, Preschool; Chondroblastoma - genetics; Chondroblastoma - pathology; Gene Expression Regulation, Neoplastic; Histones - genetics; Histones - metabolism; Humans; Individualized Instruction; Lysine - genetics; Mesenchymal Stromal Cells - metabolism; Mesenchymal Stromal Cells - pathology; Methionine - genetics; Methylation; Methyltransferases - genetics; Methyltransferases - metabolism; Mice; Mutation; Mutation, Missense; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Nucleosomes - genetics; Pediatrics; Polycomb Repressive Complex 1 - metabolism; Sarcoma - genetics; Sarcoma - pathology
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aac7272

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.