Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape Journal Article

Authors: Lu, C.; Jain, S. U.; Hoelper, D.; Bechet, D.; Molden, R. C.; Ran, L.; Murphy, D.; Venneti, S.; Hameed, M.; Pawel, B. R.; Wunder, J. S.; Dickson, B. C.; Lundgren, S. M.; Jani, K. S.; De Jay, N.; Papillon-Cavanagh, S.; Andrulis, I. L.; Sawyer, S. L.; Grynspan, D.; Turcotte, R. E.; Nadaf, J.; Fahiminiyah, S.; Muir, T. W.; Majewski, J.; Thompson, C. B.; Chi, P.; Garcia, B. A.; Allis, C. D.; Jabado, N.; Lewis, P. W.
Article Title: 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.
Journal Title: Science
Volume: 352
Issue: 6287
ISSN: 0036-8075
Publisher: American Association for the Advancement of Science  
Date Published: 2016-05-13
Start Page: 844
End Page: 849
Language: English
DOI: 10.1126/science.aac7272
PROVIDER: scopus
PUBMED: 27174990
PMCID: PMC4928577
Notes: Article -- Export Date: 2 June 2016 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Meera Hameed
    139 Hameed
  2. Ping Chi
    47 Chi
  3. Leili Ran
    17 Ran
  4. Craig Bernie Thompson
    120 Thompson
  5. Devan Anne Murphy
    11 Murphy