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Spontaneous DIPG Modeling Reveals Novel H3.3 K27M-Mediated Oncogenic Mechanisms Acting Through Epigenetic Effects

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE108364 | GEO | 2019/01/03

REPOSITORIES: GEO

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Spontaneous DIPG Modeling Reveals Novel H3.3 K27M-Mediated Oncogenic Mechanisms Acting Through Epigenetic Effects

Project description:A mouse knock-in model engineered for Cre recombinase-activated expression of the endogenous mouse H3f3a allele generating an epitope-tagged H3.3 equipped with or without a K27M mutation to investigate H3.3 K27M effects on brain cell and tumor growth, gene expression and epigenetics. These samples are matched with H3K27me3 ChIPseq and RNAseq in GSE108364.

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Spontaneous DIPG Modeling Reveals Novel H3.3 K27M-Mediated Oncogenic Mechanisms Acting Through Epigenetic Effects [ChIP-seq]

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Spontaneous DIPG Modeling Reveals Novel H3.3 K27M-Mediated Oncogenic Mechanisms Acting Through Epigenetic Effects

Project description:Spontaneous DIPG Modeling Reveals Novel H3.3 K27M-Mediated Oncogenic Mechanisms Acting Through Epigenetic Effects

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Spontaneous DIPG Modeling Reveals Novel H3.3 K27M-Mediated Oncogenic Mechanisms Acting Through Epigenetic Effects

Project description:Spontaneous DIPG Modeling Reveals Novel H3.3 K27M-Mediated Oncogenic Mechanisms Acting Through Epigenetic Effects

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Spontaneous DIPG Modeling Reveals Novel H3.3 K27M-Mediated Oncogenic Mechanisms Acting Through Epigenetic Effects [ChIP-seq]

Project description:Spontaneous DIPG Modeling Reveals Novel H3.3 K27M-Mediated Oncogenic Mechanisms Acting Through Epigenetic Effects [ChIP-seq]

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Spontaneous DIPG Modeling Reveals Novel H3.3 K27M-Mediated Oncogenic Mechanisms Acting Through Epigenetic Effects [RNA-seq]

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

Project description: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 ? (PDGFR?) 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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Human ESC-based modeling of pediatric gliomas by K27M mutation in histone H3.3 variant

Project description:Human diffuse intrinsic pontine gliomas (DIPG) are an aggressive form of pediatric brain tumors that arise in the pons in young children thus resulting in significant morbidity and very poor survival. Recent data suggest that mutations in the histone H3.3 variant are often found in these tumors, though the mechanism of their contribution to oncogenesis remains to be elucidated. Here we report that the combination of constitutive PDGFRA activation and p53 suppression as well as expression of the K27M mutant form of the histone H3.3 variant leads to neoplastic transformation of hPSC-derived neural precursors. Our study demonstrates that human ES cells represent an excellent platform for the modeling of human tumors in vitro and in vivo, which could potentially lead to the elucidation of the molecular mechanisms underlying neoplastic transformation and the identification of novel therapeutic targets. Human ES cells were differentiated to NPCs and lentivirally transduced with a combination of constitutively active PDGFRA (D842V), sh-p53, and WT or K27M mutant form of histone H3.3 variant.

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Reciprocal H3.3 gene editing identifies K27M and G34R mechanisms in pediatric glioma including NOTCH signaling.

Project description:Histone H3.3 mutations are a hallmark of pediatric gliomas, but their core oncogenic mechanisms are not well-defined. To identify major effectors, we used CRISPR-Cas9 to introduce H3.3K27M and G34R mutations into previously H3.3-wildtype brain cells, while in parallel reverting the mutations in glioma cells back to wildtype. ChIP-seq analysis broadly linked K27M to altered H3K27me3 activity including within super-enhancers, which exhibited perturbed transcriptional function. This was largely independent of H3.3 DNA binding. The K27M and G34R mutations induced several of the same pathways suggesting key shared oncogenic mechanisms including activation of neurogenesis and NOTCH pathway genes. H3.3 mutant gliomas are also particularly sensitive to NOTCH pathway gene knockdown and drug inhibition, reducing their viability in culture. Reciprocal editing of cells generally produced reciprocal effects on tumorgenicity in xenograft assays. Overall, our findings define common and distinct K27M and G34R oncogenic mechanisms, including potentially targetable pathways.

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