Cited by 212Epigenetics and DNA MethylationGenomics and Chromatin DynamicsChromatin Remodeling and Cancer

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

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Souroullas, George P, Jeck, William R, Parker, Joel S, Simon, Jeremy M, Liu, Jie-Yu, Paulk, Joshiawa, Xiong, Jessie, Clark, Kelly S +5 more·2016·Nature Medicine

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.

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  • PRMT5 has been implicated in driving neoplastic growth of multiple tumours including B cell lymphoma, multiple myeloma, breast cancer and glioblastoma.

    “More recently, the arginine methyltransferase PRMT5 has been implicated in driving neoplastic growth of multiple tumours including B cell lymphoma, multiple myeloma, breast cancer and glioblastoma 171-178 .”
  • EZH2 that is abnormally active can cooperate with hyperactive BRAF to promote tumorigenesis.

    “Furthermore, aberrantly activated EZH2 was recently found to synergistically cooperate with hyperactive BRAF in the regulation of tumorigenesis49.”
  • More EZH2 expression or activity accompanies a genome-wide shift in H3K27me3, with H3K27me3 loss and activation of many PRC2-repressed genes.

    “Increased EZH2 expression/activity is associated with a genome-wide redistribution of H3K27me3 that includes the loss of H3K27me3 and the transcriptional activation of numerous PRC2 suppressed genes in these cells49.”

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Authors
Souroullas, G. P., Jeck, W. R., Parker, J. S., Simon, J. M., Liu, J.-Y., Paulk, J., Xiong, J., Clark, K. S., Fedoriw, Y., Qi, J., Burd, C. E., Bradner, J. E., & Sharpless, N. E.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • Harvard University (US)
  • The Ohio State University (US)
Corresponding author
Sharpless, Norman E
Venue
Nature Medicine
Published
2016-05-02
Volume
22
Issue
6
Pages
632-640
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
OpenAlex
W2345827275
Cited by
212
References
58
Citations by year
2026: 9 · 2025: 11 · 2024: 17 · 2023: 26 · 2022: 26 · 2021: 22 · 2020: 25 · 2019: 20 · 2018: 18 · 2017: 23 · 2016: 14
FWCI
12.99
Type
journal article
Language
en
Open access
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • UNC Libraries
Funders
  • National Institutes of Health (5r01ag024379-15)
  • National Institute on Aging (AG024379, R01-AG024379)
  • National Heart, Lung, and Blood Institute (F32HL117581)
  • National Cancer Institute (CA163896, P01CA142106, T32CA009156, R01CA185353, R01CA163896, P30CA016058, P30CA016086)
  • National Institute of Environmental Health Sciences (P30ES010126)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
EZH2, H3K27me3, B-cell lymphoma, melanoma, gain-of-function mutations, Polycomb repression, chromatin structure, Bcl-2, p53, BRAF, NRAS, transcriptional activation, conditional mouse model
MeSH terms
Enhancer of Zeste Homolog 2 Protein, Animals, B-Lymphocytes, Humans, Melanocytes, Melanoma, Methylation, Mutation, Neoplasm Transplantation, Immunoblotting, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-myc, Lymphoma, B-Cell, Disease Progression, Proto-Oncogene Proteins c-bcl-2, Monomeric GTP-Binding Proteins, Histone Code, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Mice, Gene Knockdown Techniques, Real-Time Polymerase Chain Reaction, Carcinogenesis

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