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

Dong Fang, Haiyun Gan, Jeong Heon Lee, Jing Han, Zhiquan Wang, Scott M. Riester, Long Jin, Jianji Chen, Hui Zhou, Jinglong Wang, Honglian Zhang, Na Yang, Elizabeth Bradley, Thai H Ho, Brian P. Rubin, Julia A. Bridge, Stephen N Thibodeau, Tamas Ordog, Yue Chen, Andre J van WijnenAndre M. Oliveira, Rui Ming Xu, Jennifer J Westendorf, Zhiguo Zhang

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Abstract

More than 90% of chondroblastomas contain a heterozygous mutation replacing lysine-36 with methionine-36 (K36M) in the histone H3 variant H3.3. Here we show that H3K36 methylation is reduced globally in human 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 trimethylation 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 the H3K36 methylation landscape and contribute to tumorigenesis, in part through altering the expression of cancer-associated genes.

Original languageEnglish (US)
Pages (from-to)1344-1348
Number of pages5
JournalScience
Volume352
Issue number6291
DOIs
StatePublished - Jun 10 2016

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    Fang, D., Gan, H., Lee, J. H., Han, J., Wang, Z., Riester, S. M., Jin, L., Chen, J., Zhou, H., Wang, J., Zhang, H., Yang, N., Bradley, E., Ho, T. H., Rubin, B. P., Bridge, J. A., Thibodeau, S. N., Ordog, T., Chen, Y., ... Zhang, Z. (2016). The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. Science, 352(6291), 1344-1348. https://doi.org/10.1126/science.aae0065