Histone H3.3 K27M Accelerates Spontaneous Brainstem Glioma and Drives Restricted Changes in Bivalent Gene Expression

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 preservin...

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Published in:Cancer cell Vol. 35; no. 1; p. 140
Main Authors: Larson, Jon D, Kasper, Lawryn H, Paugh, Barbara S, Jin, Hongjian, Wu, Gang, Kwon, Chang-Hyuk, Fan, Yiping, Shaw, Timothy I, Silveira, André B, Qu, Chunxu, Xu, Raymond, Zhu, Xiaoyan, Zhang, Junyuan, Russell, Helen R, Peters, Jennifer L, Finkelstein, David, Xu, Beisi, Lin, Tong, Tinkle, Christopher L, Patay, Zoltan, Onar-Thomas, Arzu, Pounds, Stanley B, McKinnon, Peter J, Ellison, David W, Zhang, Jinghui, Baker, Suzanne J
Format: Journal Article
Language:English
Published: United States 14.01.2019
Subjects:
Animals
Brain Stem Neoplasms - genetics
Cell Self Renewal
Cells, Cultured
Epigenesis, Genetic
Gene Expression Profiling - methods
Gene Expression Regulation, Neoplastic
Glioma - genetics
Histones - genetics
Histones - metabolism
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
PDGFRA
mouse
knockin
epigenetic
histone H3 K27M
bivalent
oncohistone
glioma
DIPG
H3K27me3
ISSN:1878-3686, 1878-3686
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Summary: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.
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ISSN:1878-3686
1878-3686
DOI:10.1016/j.ccell.2018.11.015