Cancer: Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape Academic Article uri icon

Overview

MeSH Major

  • Bone Neoplasms
  • Carcinogenesis
  • Chondroblastoma
  • Histones
  • Mesenchymal Stromal Cells
  • Neoplastic Stem Cells
  • 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.

publication date

  • May 13, 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4928577

Digital Object Identifier (DOI)

  • 10.1126/science.aac7272

PubMed ID

  • 27174990

Additional Document Info

start page

  • 844

end page

  • 9

volume

  • 352

number

  • 6287