Pervasive H3K27 Acetylation Leads to ERV Expression and a Therapeutic Vulnerability in H3K27M Gliomas.
Acetylation
Brain Neoplasms
/ drug therapy
Cell Line, Tumor
Chromatin
/ metabolism
Enhancer Elements, Genetic
/ drug effects
Epigenomics
/ methods
Gene Expression Regulation, Neoplastic
/ drug effects
Glioma
/ drug therapy
Histone Deacetylase Inhibitors
/ pharmacology
Histones
/ genetics
Humans
Mutation
H3K27M
H3K27ac
enhancer
epigenetic therapy
pediatric high-grade glioma
repetitive element
viral mimicry
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
13 05 2019
13 05 2019
Historique:
received:
25
09
2018
revised:
16
01
2019
accepted:
12
04
2019
entrez:
16
5
2019
pubmed:
16
5
2019
medline:
14
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31085178
pii: S1535-6108(19)30199-0
doi: 10.1016/j.ccell.2019.04.004
pmc: PMC6521975
mid: NIHMS1527233
pii:
doi:
Substances chimiques
Chromatin
0
Histone Deacetylase Inhibitors
0
Histones
0
Types de publication
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.
Langues
eng
Sous-ensembles de citation
IM
Pagination
782-797.e8Subventions
Organisme : CIHR
ID : PJT-156086
Pays : Canada
Organisme : CIHR
ID : FDN-154307
Pays : Canada
Organisme : NCI NIH HHS
ID : P01 CA196539
Pays : United States
Organisme : CIHR
ID : EP1-120608
Pays : Canada
Organisme : CIHR
ID : MOP-286756
Pays : Canada
Organisme : NCATS NIH HHS
ID : TL1 TR001880
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008275
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI118891
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM110174
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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