Journal
CANCER CELL
Volume 35, Issue 5, Pages 782-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2019.04.004
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Funding
- US NIH [P01-CA196539, T32GM008275, TL1TR001880]
- Canadian Institutes of Health Research (CIHR) [MOP-286756, FDN-154307, PJT-156086]
- Fonds de Recherche du Quebec en Sante (FRQS)
- FRQS
- Genome Canada
- Genome Quebec
- Cancer Prevention Research Institute of Texas (CPRIT) scholar award [RR170023]
- Alex's Lemonade Stand Foundation (ALSF) A award
- BEAR Necessities Pediatric Cancer Foundation
- Children's Cancer Research Fund award
- Children's Brain Tumor Foundation Award
- Baylor College of Medicine Junior Faculty Award
- CIHR Banting postdoctoral fellowship
- Young investigator award
- RALLY research grant
- NATIONAL CANCER INSTITUTE [P01CA196539] Funding Source: NIH RePORTER
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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.
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