Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape.

TitleHistone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape.
Publication TypeJournal Article
Year of Publication2016
AuthorsLu, C, Jain, SU, Hoelper, D, Bechet, D, Molden, RC, Ran, L, Murphy, D, Venneti, S, Hameed, M, Pawel, BR, Wunder, JS, Dickson, BC, Lundgren, SM, Jani, KS, De Jay, N, Papillon-Cavanagh, S, Andrulis, IL, Sawyer, SL, Grynspan, D, Turcotte, RE, Nadaf, J, Fahiminiyah, S, Muir, TW, Majewski, J, Thompson, CB, Chi, P, Garcia, BA, C Allis, D, Jabado, N, Lewis, PW
JournalScience
Volume352
Issue6287
Pagination844-9
Date Published2016 May 13
ISSN1095-9203
KeywordsAnimals, Bone Neoplasms, Carcinogenesis, Child, Preschool, Chondroblastoma, Gene Expression Regulation, Neoplastic, Histones, Humans, Lysine, Mesenchymal Stromal Cells, Methionine, Methylation, Methyltransferases, Mice, Mutation, Mutation, Missense, Neoplastic Stem Cells, Nucleosomes, Polycomb Repressive Complex 1, Sarcoma
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.

DOI10.1126/science.aac7272
Alternate JournalScience
PubMed ID27174990
PubMed Central IDPMC4928577
Grant ListP01CA196539 / CA / NCI NIH HHS / United States
K08 CA181475 / CA / NCI NIH HHS / United States
K08CA181475 / CA / NCI NIH HHS / United States
P01 CA196539 / CA / NCI NIH HHS / United States
DP2OD007447 / OD / NIH HHS / United States
K08CA151660 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
R01GM110174 / GM / NIGMS NIH HHS / United States
P30CA008748 / CA / NCI NIH HHS / United States
DP2 OD007447 / OD / NIH HHS / United States
R01 GM110174 / GM / NIGMS NIH HHS / United States
DP2CA174499 / CA / NCI NIH HHS / United States
DP2 CA174499 / CA / NCI NIH HHS / United States
K08 CA151660 / CA / NCI NIH HHS / United States