@article{10451be47d2047c490b5d6b87e3738d4,
title = "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.",
keywords = "H3K27M, H3K27ac, enhancer, epigenetic therapy, pediatric high-grade glioma, repetitive element, viral mimicry",
author = "Brian Krug and {De Jay}, Nicolas and Harutyunyan, {Ashot S.} and Shriya Deshmukh and Marchione, {Dylan M.} and Paul Guilhamon and Bertrand, {Kelsey C.} and Mikael, {Leonie G.} and McConechy, {Melissa K.} and Chen, {Carol C.L.} and Sima Khazaei and Koncar, {Robert F.} and Sameer Agnihotri and Damien Faury and Benjamin Ellezam and Weil, {Alexander G.} and Josie Ursini-Siegel and {De Carvalho}, {Daniel D.} and Dirks, {Peter B.} and Lewis, {Peter W.} and Paolo Salomoni and Mathieu Lupien and Cheryl Arrowsmith and Lasko, {Paul F.} and Garcia, {Benjamin A.} and Kleinman, {Claudia L.} and Nada Jabado and Mack, {Stephen C.}",
note = "Funding Information: We thank Jacek Majewski for invaluable guidance in experimental design and critical reading of manuscript. We thank Alexey Soshnev for creating Figure 8 . This work was supported by funding from: US NIH (grant P01-CA196539 to N.J., P.W.L., and B.A.G.; and T32GM008275 and TL1TR001880 to B.A.G.), the Canadian Institutes of Health Research (CIHR grant MOP-286756 and FDN-154307 to N.J., EP1-120608 to T.P., and PJT-156086 to C.L.K.), the Fonds de Recherche du Qu{\'e}bec en Sant{\'e} (FRQS) salary award to C.L.K. and fellowships to N.D.J. and A.S.H. N.J. is a member of the Penny Cole Laboratory and the recipient of a Chercheur Boursier, Chaire de Recherche Award from the FRQS. This work was performed within the context of the International CHildhood Astrocytoma INtegrated Genomic and Epigenomic (ICHANGE) consortium with funding from Genome Canada and G{\'e}nome Qu{\'e}bec . Computational infrastructure was provided by Compute Canada and Calcul Qu{\'e}bec. M.K.M. is funded by a CIHR Banting postdoctoral fellowship. P.W.L. is a Pew Scholar in the Biomedical Sciences. We are especially grateful for the generous philanthropic donations of Kat D DIPG, Poppies for Irene and We Love You Connie Foundations. S.C.M. is supported by Cancer Prevention Research Institute of Texas (CPRIT) scholar award ( RR170023 ), Alex{\textquoteright}s Lemonade Stand Foundation (ALSF) A award, and Young investigator award, RALLY research grant, BEAR Necessities Pediatric Cancer Foundation Grant, Children's Cancer Research Fund award, Children's Brain Tumor Foundation Award, and Baylor College of Medicine Junior Faculty Award. Funding Information: We thank Jacek Majewski for invaluable guidance in experimental design and critical reading of manuscript. We thank Alexey Soshnev for creating Figure 8. This work was supported by funding from: US NIH (grant P01-CA196539 to N.J. P.W.L. and B.A.G.; and T32GM008275 and TL1TR001880 to B.A.G.), the Canadian Institutes of Health Research (CIHR grant MOP-286756 and FDN-154307 to N.J. EP1-120608 to T.P. and PJT-156086 to C.L.K.), the Fonds de Recherche du Qu{\'e}bec en Sant{\'e} (FRQS)salary award to C.L.K. and fellowships to N.D.J. and A.S.H. N.J. is a member of the Penny Cole Laboratory and the recipient of a Chercheur Boursier, Chaire de Recherche Award from the FRQS. This work was performed within the context of the International CHildhood Astrocytoma INtegrated Genomic and Epigenomic (ICHANGE)consortium with funding from Genome Canada and G{\'e}nome Qu{\'e}bec. Computational infrastructure was provided by Compute Canada and Calcul Qu{\'e}bec. M.K.M. is funded by a CIHR Banting postdoctoral fellowship. P.W.L. is a Pew Scholar in the Biomedical Sciences. We are especially grateful for the generous philanthropic donations of Kat D DIPG, Poppies for Irene and We Love You Connie Foundations. S.C.M. is supported by Cancer Prevention Research Institute of Texas (CPRIT)scholar award (RR170023), Alex's Lemonade Stand Foundation (ALSF)A award, and Young investigator award, RALLY research grant, BEAR Necessities Pediatric Cancer Foundation Grant, Children's Cancer Research Fund award, Children's Brain Tumor Foundation Award, and Baylor College of Medicine Junior Faculty Award. B.K. and A.S.H. led and performed a majority of the functional studies, and were actively involved in study design, data analysis, interpretation, and manuscript preparation. N.D.J. led the bioinformatics analysis, and also was actively involved in study design, data analysis, interpretation, and manuscript preparation. S.D. M.K.McC. C.C.L.C. and D.F. contributed to data collection, analysis, and study design. D.M.M. and B.G. led the histone proteomics experiments and analysis. P.G. and M.L. led the ATAC-seq analysis. K.C.B. contributed to enhancer analysis, figure preparation, and data processing. L.G.M. contributed to study design, data interpretation, and manuscript preparation. B.E. and A.G.W. assisted with the collection of patient samples, study design and data interpretation. D.D.d.C. led the analysis and data interpretation regarding repeat element and ERV analysis. P.S. generated the mouse model used for cross-species validation of repeat element expression. P.B.D. D.W.P. D.G.P. S.M.P. P.L. M.L. C.A. B.A.G. C.L.K. N.J. and S.C.M. contributed to study design, data interpretation, and manuscript preparation. C.L.K. N.J. and S.C.M. co-led and supervised all aspects the project. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = may,
day = "13",
doi = "10.1016/j.ccell.2019.04.004",
language = "English",
volume = "35",
pages = "782--797.e8",
journal = "Cancer Cell",
issn = "1535-6108",
number = "5",
}