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Pervasive H3K27 Acetylation Leads to ERV Expression and a Therapeutic Vulnerability in H3K27M Gliomas.

Abstract
High-grade gliomas defined by histone 3 K27M driver mutations exhibit global loss of H3K27 trimethylation and reciprocal gain of H3K27 acetylation, respectively shaping repressive and active chromatin landscapes. We generated tumor-derived isogenic models bearing this mutation and show that it leads to pervasive H3K27ac deposition across the genome. In turn, active enhancers and promoters are not created de novo and instead reflect the epigenomic landscape of the cell of origin. H3K27ac is enriched at repeat elements, resulting in their increased expression, which in turn can be further amplified by DNA demethylation and histone deacetylase inhibitors providing an exquisite therapeutic vulnerability. These agents may therefore modulate anti-tumor immune responses as a therapeutic modality for this untreatable disease.
AuthorsBrian Krug, Nicolas De Jay, Ashot S Harutyunyan, Shriya Deshmukh, Dylan M Marchione, Paul Guilhamon, Kelsey C Bertrand, Leonie G Mikael, Melissa K McConechy, Carol C L Chen, Sima Khazaei, Robert F Koncar, Sameer Agnihotri, Damien Faury, Benjamin Ellezam, Alexander G Weil, Josie Ursini-Siegel, Daniel D De Carvalho, Peter B Dirks, Peter W Lewis, Paolo Salomoni, Mathieu Lupien, Cheryl Arrowsmith, Paul F Lasko, Benjamin A Garcia, Claudia L Kleinman, Nada Jabado, Stephen C Mack
JournalCancer cell (Cancer Cell) Vol. 35 Issue 5 Pg. 782-797.e8 (05 13 2019) ISSN: 1878-3686 [Electronic] United States
PMID31085178 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
CopyrightCopyright © 2019 Elsevier Inc. All rights reserved.
Chemical References
  • Chromatin
  • Histone Deacetylase Inhibitors
  • Histones
Topics
  • Acetylation
  • Brain Neoplasms (drug therapy, genetics, metabolism)
  • Cell Line, Tumor
  • Chromatin (metabolism)
  • Enhancer Elements, Genetic (drug effects)
  • Epigenomics (methods)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Glioma (drug therapy, genetics, metabolism)
  • Histone Deacetylase Inhibitors (pharmacology, therapeutic use)
  • Histones (genetics, metabolism)
  • Humans
  • Mutation

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