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H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo [ChIP-Seq]

ABSTRACT: H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo [ChIP-Seq]

PROVIDER: PRJNA476346 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7348490.fastq.gz	Fastqsanger.gz
	SRR7348500.fastq.gz	Fastqsanger.gz
	SRR7348510.fastq.gz	Fastqsanger.gz
	SRR7348520.fastq.gz	Fastqsanger.gz
	SRR7348530.fastq.gz	Fastqsanger.gz

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H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo

Project description:H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo

| PRJNA476344 | ENA

H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo

Project description:Xenografts from human pediatric brainstem gliomas bearing K27M in H3F3A were transduced with non silencing or H3F3A shRNA to assess the impact of the K27M on tumor growth, gene expression and epigenetics

2019-03-18 | GSE115875 | GEO

H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo [RNA-Seq]

Project description:H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo [RNA-Seq]

| PRJNA476347 | ENA

H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo [RNA-Seq]

Project description:xenografts from human pediatric brainstem gliomas bearing K27M in H3F3A were transduced with non silencing or H3F3A shRNA to assess the impact of the K27M on tumor growth, gene expression and epigenetics

2019-03-18 | GSE115873 | GEO

H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo [ChIP-Seq]

2019-03-18 | GSE115872 | GEO

H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo.

Project description:Histone H3 K27M mutation is the defining molecular feature of the devastating pediatric brain tumor, diffuse intrinsic pontine glioma (DIPG). The prevalence of histone H3 K27M mutations indicates a critical role in DIPGs, but the contribution of the mutation to disease pathogenesis remains unclear. We show that knockdown of this mutation in DIPG xenografts restores K27M-dependent loss of H3K27me3 and delays tumor growth. Comparisons of matched DIPG xenografts with and without K27M knockdown allowed identification of mutation-specific effects on the transcriptome and epigenome. The resulting transcriptional changes recapitulate expression signatures from K27M primary DIPG tumors and are strongly enriched for genes associated with nervous system development. Integrated analysis of ChIP-seq and expression data showed that genes upregulated by the mutation are overrepresented in apparently bivalent promoters. Many of these targets are associated with more immature differentiation states. Expression profiles indicate K27M knockdown decreases proliferation and increases differentiation within lineages represented in DIPG. These data suggest that K27M-mediated loss of H3K27me3 directly regulates a subset of genes by releasing poised promoters, and contributes to tumor phenotype and growth by limiting differentiation. The delayed tumor growth associated with knockdown of H3 K27M provides evidence that this highly recurrent mutation is a relevant therapeutic target.

| S-EPMC6546611 | biostudies-literature

Correction to: H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo.

Project description:The original article can be found online.

| S-EPMC6999025 | biostudies-literature

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.

2014-11-21 | E-GEOD-55541 | biostudies-arrayexpress

Histone H3.3 K27M chromatin functions implicate a network of neurodevelopmental factors including ASCL1 and NEUROD1 in DIPG

Project description:Background: The histone variant H3.3 K27M mutation is a defining characteristic of diffuse intrinsic pontine glioma (DIPG)/diffuse midline glioma (DMG). This histone mutation is responsible for major alterations to histone H3 post-translational modification (PTMs) and subsequent aberrant gene expression. However, much less is known about the effect this mutation has on chromatin structure and function, including open versus closed chromatin regions as well as their transcriptomic consequences. Results: Recently, we developed isogenic CRISPR-edited DIPG cell lines that are wild- type for histone H3.3 that can be compared to their matched K27M lines. Here we show via ATAC-seq analysis that H3.3K27M glioma cells have unique accessible chromatin at regions corresponding to neurogenesis, NOTCH, and neuronal development pathways and associated genes that are overexpressed in H3.3K27M compared to our isogenic wild-type cell line. As to mechanisms, accessible enhancers and super-enhancers corresponding to increased gene expression in H3.3K27M cells were also mapped to genes involved in neurogenesis and NOTCH signaling, suggesting that these pathways are key to DIPG tumor maintenance. Motif analysis implicates specific transcription factors as central to the neuro-oncogenic K27M signaling pathway including, in particular, ASCL1 and NEUROD1. Conclusions: Altogether our findings indicate that H3.3K27M causes chromatin to take on a more accessible configuration at key regulatory regions for NOTCH and neurogenesis genes resulting in increased oncogenic gene expression, which is at least partially reversible upon editing K27M back to wild- type.

2022-04-24 | GSE201265 | GEO

Illumina Infinium 450K array data for Diffuse Intrinsic Pontine Glioma

Project description:Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and choosing therapies based on assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic make-up of this brain cancer with nearly 80% harboring a K27M-H3.3 or K27M-H3.1 mutation. However, DIPGs are still thought of as one disease with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs we integrated whole-genome-sequencing with methylation, expression and copy-number profiling, discovering that DIPGs are three molecularly distinct subgroups (H3-K27M, Silent, MYCN) and uncovering a novel recurrent activating mutation in the activin receptor ACVR1, in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer. Illumina Infinium 450K arrays were performed according to the manufacturer's directions on bisulfite converted gDNA extracted from fresh frozen biopsy and autopsy brain tissue from DIPG patients. CpG methylation profiling on Illumina Infinium 450K arrays was performed for 28 paediatric DIPG samples.

2014-03-31 | E-GEOD-50022 | biostudies-arrayexpress

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