title: An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation.
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.
authors.affiliation: Department of Genetics, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: George P
authors.initials: GP
authors.lastname: Souroullas
authors.affiliation: Department of Genetics, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Jeck
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.affiliation: Department of Genetics, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Jeremy M
authors.identifier: 0000-0003-3906-1663
authors.initials: JM
authors.lastname: Simon
authors.affiliation: Department of Genetics, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Jie-Yu
authors.initials: JY
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Joshiawa
authors.initials: J
authors.lastname: Paulk
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Jessie
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Clark
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.|Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Fedoriw
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Molecular Genetics, Ohio State University, Columbus, Ohio, USA.|Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio, USA.
authors.forename: Christin E
authors.initials: CE
authors.lastname: Burd
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Genetics, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055785:Gene Knockdown Techniques; D042421:Histone Code / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics*; D008745:Methylation; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics; D009154:Mutation; D009368:Neoplasm Transplantation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C489428:Myc protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; C052617:Bcl2 protein, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D020559:Monomeric GTP-Binding Proteins; C586503:Nras protein, mouse