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Gene expression data of pHGG tumor samples

ABSTRACT: Pediatric high-grade gliomas (pHGGs) harboring the K27M mutation of H3F3A (histone H3.3) are characterized by global reduction of the repressive histone mark H3K27me3 and DNA hypomethylation. Analysis of K27M-induced changes on H3K27me3 occupancy and DNA methylation at differentially expresed genes (K27M vs. wild-type H3.3) in primary pHGG tumor samples.

ORGANISM(S): Homo sapiens

PROVIDER: GSE49822 | GEO | 2014/05/14

SECONDARY ACCESSION(S): PRJNA215022

REPOSITORIES: GEO

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Gene expression data of pHGG tumor samples

Project description:Pediatric high-grade gliomas (pHGGs) harboring the K27M mutation of H3F3A (histone H3.3) are characterized by global reduction of the repressive histone mark H3K27me3 and DNA hypomethylation. Analysis of K27M-induced changes on H3K27me3 occupancy and DNA methylation at differentially expresed genes (K27M vs. wild-type H3.3) in primary pHGG tumor samples. 22 glioblastoma samples from pHGG patients were selected for RNA extraction and hybridization on Affymetrix Affymetrix Human Genome U133 Plus 2.0 Arrays. Expression profiling data of 17 pHHGs are part of our previous study (GSE36245 or GSE34824).

2014-05-14 | E-GEOD-49822 | biostudies-arrayexpress

Aberrant DNA repair reveals a vulnerability in histone H3.3-mutant brain tumors

Project description:Pediatric high-grade gliomas (pHGG) are devastating and incurable brain tumors with recurrent mutations in histone H3.3. These mutations promote oncogenesis by dysregulating gene expression through alterations of histone modifications. We identify aberrant DNA repair as an independent mechanism, which fosters genome instability in H3.3 mutant pHGG, and opens new therapeutic options. The two most frequent H3.3 mutations in pHGG, K27M and G34R, drive aberrant repair of replication-associated damage by non-homologous end joining (NHEJ). Aberrant NHEJ is mediated by the DNA repair enzyme Polynucleotide Kinase 3'-Phosphatase (PNKP), which shows increased association with mutant H3.3 at damaged replication forks. PNKP sustains the proliferation of cells bearing H3.3 mutations, thus conferring a molecular vulnerability, specific to mutant cells, with potential for therapeutic targeting.

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Novel genetically engineered H3.3G34R model reveals cooperation with ATRX loss in upregulation of PRC2 targets, NOTCH activation, promotion of neuronal lineage

Project description:Pediatric high-grade gliomas (pHGGs) are an aggressive pediatric CNS tumor, often characterized by mutations in H3F3A, the gene that encodes Histone H3.3 (H3.3). Substitution of the Glycine at position 34 of H3.3 with either Arginine or Valine (H3.3G34R/V), was recently described and characterized in a large cohort of pHGG samples as occurring in 5-20% of pHGGs. We developed a genetically engineered mouse model (GEMM) that incorporates PDGF-A activation, TP53 loss and the H3.3G34R mutation both in the presence and loss of Alpha thalassemia/mental retardation syndrome X-linked (ATRX), which is commonly mutated in H3.3G34 mutant pHGGs. Nestin Tv-a; p53 fl/fl and Nestin Tv-a; p53 fl/fl; ATRX fl/fl mice were injected with DF-1 cells transfected with RCAS-Cre, RCAS-PDGFA, and either RCAS-H3.3WT-GFP or RCAS-H3.3G34R-GFP. By 210 days old, a majority of mice develop symptoms of tumor growth (erratic behavior, domed head, ataxia) or have 20% weight loss and are euthanized. Our goal is to develop a biologically relevant animal model of pHGG in order to probe the downstream effects of the H3.3G34R mutation in the context of vital co-occurring mutations.

2023-03-04 | GSE197988 | GEO

Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M-mutant pediatric high-grade gliomas

Project description:Genome-wide analysis of H3K27me3 occupancy and DNA methylation in K27M-mutant and H3.3-WT primary pediatric high-grade gliomas (pHGGs) as well as pediatric pHGG cell lines. The study aims to elucidate the connection between K27M-induced H3K27me3 reduction and changes in DNA methylation as well as gene expression.

| EGAS00001000578 | EGA

ena-DATASET-DKFZ-IBIOS-15-10-2013-14:26:06:568-481 - samples

| EGAD00001000677 | EGA

Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants [ChIP-Seq]

Project description:Point mutations within the histone H3.3 are frequent in aggressive childhood brain tumours known as paediatric high-grade gliomas (pHGGs). Intriguingly, different mutations arise in discrete anatomical regions: H3.3-G34R within the forebrain and H3.3-K27M preferentially within the hindbrain. The reasons for this contrasting aetiology are unknown. By engineering human foetal neural stem cell cultures from distinct regions, we demonstrate here that cell-intrinsic regional identity provides differential responsiveness to each mutant that mirrors the origins of pHGGs. Focusing on H3.3-G34R, we find that the oncohistone supports proliferation of forebrain cells, while inducing a cytostatic response in the hindbrain. Mechanistically, H3.3-G34R does not impose widespread transcriptional or epigenetic changes, but impairs recruitment of ZMYND11, a transcriptional repressor of highly expressed genes. We therefore propose that H3.3-G34R promotes tumorigenesis by stabilising the expression of key progenitor genes and, thus, locking initiating forebrain cells into their preexisting immature state.

2021-03-24 | GSE163185 | GEO

Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants [RNA-Seq]

2021-03-24 | GSE163044 | GEO

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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.

2022-05-17 | GSE171802 | GEO

The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression

Project description:Recent studies have identified a Lys 27-to-methionine (K27M) mutation at one allele of H3F3A, one of the two genes encoding histone H3 variant H3.3, in 60% of high-grade pediatric glioma cases. The median survival of this group of patients after diagnosis is ∼1 yr. Here we show that the levels of H3K27 di- and trimethylation (H3K27me2 and H3K27me3) are reduced globally in H3.3K27M patient samples due to the expression of the H3.3K27M mutant allele. Remarkably, we also observed that H3K27me3 and Ezh2 (the catalytic subunit of H3K27 methyltransferase) at chromatin are dramatically increased locally at hundreds of gene loci in H3.3K27M patient cells. Moreover, the gain of H3K27me3 and Ezh2 at gene promoters alters the expression of genes that are associated with various cancer pathways. These results indicate that H3.3K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumorigenesis. We performed chromatin-immunoprecipitation of H3K27me3, H3K4me3, and EZH2 in SF7761 and NSC cell lines. And do RNA-seq in SF7761, SF8828 and NSC cell lines. SF7761 and SF8628 cell lines from patients harboring the histone H3.3 K27M mutation were obtained from Hashizume et al. (2012). NSCs (N7800-100) were purchased from Invitrogen and cultured and maintained in NSC medium (A10509-01, StemPro NSC SFM, Invitrogen).

2014-09-20 | E-GEOD-61586 | biostudies-arrayexpress

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

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