An oncogenic Ezh2 mutation cooperates with particular genetic alterations to induce tumors in mice and redistributes H3K27 trimethylation throughout the genome
Souroullas, George P.
Jeck, William R.
Parker, Joel S.
Simon, Jeremy M.
Clark, Kelly S.
Burd, Christin E.
Sharpless, Norman E.Note: Order does not necessarily reflect citation order of authors.
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CitationSouroullas, G. P., W. R. Jeck, J. S. Parker, J. M. Simon, J. Liu, J. Paulk, J. Xiong, et al. 2016. “An oncogenic Ezh2 mutation cooperates with particular genetic alterations to induce tumors in mice and redistributes H3K27 trimethylation throughout the genome.” Nature medicine 22 (6): 632-640. doi:10.1038/nm.4092. http://dx.doi.org/10.1038/nm.4092.
AbstractB-cell lymphoma and melanoma harbor recurrent mutations in the gene encoding the EZH2 histone methyltransferase, but the carcinogenic role of these mutations is unclear. Here we describe a mouse model in which the most common somatic EZH2 gain-of-function mutation (Y646F in human, Y641F in the mouse) can be conditionally expressed. Expression of Ezh2Y641F in mouse B-cells or melanocytes caused high-penetrance lymphoma or melanoma, respectively. Bcl2 overexpression or p53 loss, but not c-Myc overexpression, further accelerated lymphoma progression, and expression of mutant B-Raf but not mutant N-Ras further accelerated melanoma progression. Although expression of Ezh2Y641F increased abundance of global H3K27 trimethylation (H3K27me3), it also caused a widespread redistribution of this repressive mark, including a loss of H3K27me3 associated with increased transcription at many loci. These results suggest that Ezh2Y641F induces lymphoma and melanoma through a vast reorganization of chromatin structure inducing both repression and activation of polycomb-regulated loci.
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