The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas

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Science  26 May 2016:
DOI: 10.1126/science.aae0065

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Over 90% of chondroblastomas contain a heterozygous mutation replacing lysine 36 with methionine (K36M) in the histone H3 variant H3.3. Here, we show that H3K36 methylation is reduced globally in chondroblastomas and in chondrocytes harboring the same genetic mutation due to inhibition of at least two H3K36 methyltransferases, MMSET and SETD2, by the H3.3K36M mutant proteins. Genes with altered expression as well as H3K36 di- and tri-methylation in H3.3K36M cells are enriched in cancer pathways. In addition, H3.3K36M chondrocytes exhibit several hallmarks of cancer cells including increased ability to form colonies, resistance to apoptosis and defects in differentiation. Thus, H3.3K36M proteins reprogram H3K36 methylation landscape and contribute to tumorigenesis in part through altering the expression of cancer-associated genes.

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