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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Vydané v:	Cancer cell Ročník 35; číslo 1; s. 140
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 14.01.2019
Predmet:	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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Abstract	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.
AbstractList	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. 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.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.
Author	Jin, Hongjian Xu, Raymond Kwon, Chang-Hyuk Baker, Suzanne J Onar-Thomas, Arzu McKinnon, Peter J Shaw, Timothy I Qu, Chunxu Tinkle, Christopher L Zhang, Jinghui Fan, Yiping Zhang, Junyuan Patay, Zoltan Pounds, Stanley B Wu, Gang Silveira, André B Lin, Tong Paugh, Barbara S Xu, Beisi Larson, Jon D Peters, Jennifer L Finkelstein, David Kasper, Lawryn H Ellison, David W Russell, Helen R Zhu, Xiaoyan
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SubjectTerms	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
Title	Histone H3.3 K27M Accelerates Spontaneous Brainstem Glioma and Drives Restricted Changes in Bivalent Gene Expression
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