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Nat Med. 2016 Jun;22(6):632-40. doi: 10.1038/nm.4092. Epub 2016 May 2.

An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation.

Author information

1
Department of Genetics, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina, USA.
2
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
5
Department of Molecular Genetics, Ohio State University, Columbus, Ohio, USA.
6
Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio, USA.
7
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

B cell lymphoma and melanoma harbor recurrent mutations in the gene encoding the EZH2 histone methyltransferase (EZH2), 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 (EZH2(Y646F) in human; Ezh2(Y641F) in mouse) is conditionally expressed. Expression of Ezh2(Y641F) in mouse B cells or melanocytes caused high-penetrance lymphoma or melanoma, respectively. Overexpression of the anti-apoptotic protein Bcl2, but not the oncoprotein Myc, or loss of the tumor suppressor protein p53 (encoded by Trp53 in mice) further accelerated lymphoma progression. Expression of the mutant Braf but not the mutant Nras oncoprotein further accelerated melanoma progression. Although expression of Ezh2(Y641F) globally increased the abundance of trimethylated Lys27 of histone H3 (H3K27me3), it also caused a widespread redistribution of this repressive mark, including a loss of H3K27me3 that was associated with increased transcription at many loci. These results suggest that Ezh2(Y641F) induces lymphoma and melanoma through a vast reorganization of chromatin structure, inducing both repression and activation of polycomb-regulated loci.

PMID:
27135738
PMCID:
PMC4899144
DOI:
10.1038/nm.4092
[Indexed for MEDLINE]
Free PMC Article

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