Histone H3.3 K27M Accelerates Spontaneous Brainstem Glioma and Drives Restricted Changes in Bivalent Gene Expression.
Animals
Brain Stem Neoplasms
/ genetics
Cell Self Renewal
Cells, Cultured
Epigenesis, Genetic
Gene Expression Profiling
/ methods
Gene Expression Regulation, Neoplastic
Glioma
/ genetics
Histones
/ genetics
Humans
Mice
Mutation
Neural Stem Cells
/ cytology
Receptor, Platelet-Derived Growth Factor alpha
/ genetics
Rhombencephalon
/ pathology
Sequence Analysis, RNA
/ methods
Tumor Suppressor Protein p53
/ genetics
DIPG
H3K27me3
PDGFRA
bivalent
epigenetic
glioma
histone H3 K27M
knockin
mouse
oncohistone
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
14 01 2019
14 01 2019
Historique:
received:
27
06
2018
revised:
13
10
2018
accepted:
23
11
2018
pubmed:
1
1
2019
medline:
19
10
2019
entrez:
1
1
2019
Statut:
ppublish
Résumé
Diffuse intrinsic pontine gliomas (DIPGs) are incurable childhood brainstem tumors with frequent histone H3 K27M mutations and recurrent alterations in PDGFRA and TP53. We generated genetically engineered inducible mice and showed that H3.3 K27M enhanced neural stem cell self-renewal while preserving regional identity. Neonatal induction of H3.3 K27M cooperated with activating platelet-derived growth factor receptor α (PDGFRα) mutant and Trp53 loss to accelerate development of diffuse brainstem gliomas that recapitulated human DIPG gene expression signatures and showed global changes in H3K27 posttranslational modifications, but relatively restricted gene expression changes. Genes upregulated in H3.3 K27M tumors were enriched for those associated with neural development where H3K27me3 loss released the poised state of apparently bivalent promoters, whereas downregulated genes were enriched for those encoding homeodomain transcription factors.
Identifiants
pubmed: 30595505
pii: S1535-6108(18)30536-1
doi: 10.1016/j.ccell.2018.11.015
pmc: PMC6570409
mid: NIHMS1017264
pii:
doi:
Substances chimiques
Histones
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Receptor, Platelet-Derived Growth Factor alpha
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
140-155.e7Subventions
Organisme : NCI NIH HHS
ID : R50 CA211481
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188516
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS037956
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA021765
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA096832
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2018 Elsevier Inc. All rights reserved.
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