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

Brian 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. LewisPaolo Salomoni, Mathieu Lupien, Cheryl Arrowsmith, Paul F. Lasko, Benjamin A. Garcia, Claudia L. Kleinman, Nada Jabado, Stephen C. Mack

Research output: Contribution to journalArticlepeer-review

88 Scopus citations


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.

Original languageEnglish
Pages (from-to)782-797.e8
JournalCancer Cell
Issue number5
StatePublished - May 13 2019


  • H3K27M
  • H3K27ac
  • enhancer
  • epigenetic therapy
  • pediatric high-grade glioma
  • repetitive element
  • viral mimicry


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