| Literature DB >> 30595505 |
Jon D Larson1, Lawryn H Kasper1, Barbara S Paugh1, Hongjian Jin2, Gang Wu2, Chang-Hyuk Kwon1, Yiping Fan2, Timothy I Shaw2, André B Silveira1, Chunxu Qu3, Raymond Xu1, Xiaoyan Zhu1, Junyuan Zhang1, Helen R Russell4, Jennifer L Peters5, David Finkelstein2, Beisi Xu2, Tong Lin6, Christopher L Tinkle7, Zoltan Patay8, Arzu Onar-Thomas6, Stanley B Pounds6, Peter J McKinnon4, David W Ellison3, Jinghui Zhang2, Suzanne J Baker9.
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.Entities:
Keywords: DIPG; H3K27me3; PDGFRA; bivalent; epigenetic; glioma; histone H3 K27M; knockin; mouse; oncohistone
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Year: 2018 PMID： 30595505 PMCID： PMC6570409 DOI： 10.1016/j.ccell.2018.11.015
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743