| Literature DB >> 27174990 |
Chao Lu1, Siddhant U Jain2, Dominik Hoelper2, Denise Bechet3, Rosalynn C Molden4, Leili Ran5, Devan Murphy5, Sriram Venneti6, Meera Hameed7, Bruce R Pawel8, Jay S Wunder9, Brendan C Dickson10, Stefan M Lundgren2, Krupa S Jani11, Nicolas De Jay3, Simon Papillon-Cavanagh3, Irene L Andrulis12, Sarah L Sawyer13, David Grynspan13, Robert E Turcotte14, Javad Nadaf3, Somayyeh Fahiminiyah3, Tom W Muir11, Jacek Majewski3, Craig B Thompson15, Ping Chi16, Benjamin A Garcia17, C David Allis18, Nada Jabado19, Peter W Lewis20.
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.Entities:
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Year: 2016 PMID： 27174990 PMCID： PMC4928577 DOI： 10.1126/science.aac7272
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728