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

Publication ,  Journal Article
Souroullas, GP; Jeck, WR; Parker, JS; Simon, JM; Liu, J-Y; Paulk, J; Xiong, J; Clark, KS; Fedoriw, Y; Qi, J; Burd, CE; Bradner, JE; Sharpless, NE
Published in: Nat Med
June 2016

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.

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Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

June 2016

Volume

22

Issue

6

Start / End Page

632 / 640

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Real-Time Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-myc
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins B-raf
  • Neoplasm Transplantation
  • Mutation
  • Monomeric GTP-Binding Proteins
  • Mice
  • Methylation
 

Citation

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Souroullas, G. P., Jeck, W. R., Parker, J. S., Simon, J. M., Liu, J.-Y., Paulk, J., … Sharpless, N. E. (2016). An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med, 22(6), 632–640. https://doi.org/10.1038/nm.4092
Souroullas, George P., William R. Jeck, Joel S. Parker, Jeremy M. Simon, Jie-Yu Liu, Joshiawa Paulk, Jessie Xiong, et al. “An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation.Nat Med 22, no. 6 (June 2016): 632–40. https://doi.org/10.1038/nm.4092.
Souroullas GP, Jeck WR, Parker JS, Simon JM, Liu J-Y, Paulk J, et al. An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med. 2016 Jun;22(6):632–40.
Souroullas, George P., et al. “An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation.Nat Med, vol. 22, no. 6, June 2016, pp. 632–40. Pubmed, doi:10.1038/nm.4092.
Souroullas GP, Jeck WR, Parker JS, Simon JM, Liu J-Y, Paulk J, Xiong J, Clark KS, Fedoriw Y, Qi J, Burd CE, Bradner JE, Sharpless NE. An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med. 2016 Jun;22(6):632–640.

Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

June 2016

Volume

22

Issue

6

Start / End Page

632 / 640

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Real-Time Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-myc
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins B-raf
  • Neoplasm Transplantation
  • Mutation
  • Monomeric GTP-Binding Proteins
  • Mice
  • Methylation