Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA150243 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Sequence reads for pediatric GBM samples for manuscript: Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma
| EGAD00001000134 | EGA
Project description:Point mutations in histone variant H3.3 (H3.3 K27M, H3.3 G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in paediatric gliomas. It is clear that H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are an area of active investigation. Histone H3.3 has been previously linked to PML, a gene which is frequently mutated in Acute Promyelocytic Leukaemia. We find that H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to PML-mutated Acute Promyelocytic Leukaemias, H3.3-mutated patient-derived gliomas cells are also sensitive to drugs which target PML bodies. We identify PML as a contributor to oncogenesis in H3.3-mutated gliomas and our results indicate that PML-targeting strategies may prove effective at treating H3.3-mutated paediatric gliomas.
2023-11-19 | GSE210190 | GEO
Project description:Whole exome sequencing identified frequent driver mutations in a series of paediatric glioblastomas We used microarray-based profiling to investigate differences in gene expression according to mutational status of driver genes
2012-03-01 | GSE34824 | GEO
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
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 | GSE163044 | GEO
Project description:Whole exome sequencing identified frequent driver mutations in a series of paediatric glioblastomas We used microarray-based profiling to investigate differences in gene expression according to mutational status of driver genes RNA from 27 primary tumor samples was subject to QC by Agilent BioAnalyser analysis and then hybridised to an Affymetrix U133 Plus2 gene expression array
2012-03-01 | E-GEOD-34824 | biostudies-arrayexpress
Project description:Sequencing of paediatric gliomas has identified two common substitution mutations (K27M and G34R) in genes encoding histone H3.3. We introduced a single-copy H3.3 G34R targeted mutation in mouse ES cells and observed gains in H3K36me3 and H3K9me3 across the genome. Altered chromatin profiles correlated with enrichment of KDM4 A/B/C, a histone lysine (K9/K36) demethylase. RNA-seq of H3.3 G34R mutant showed disrupted gene expression patterns which also correlated with KDM4 enrichment. Expression of a single copy of H3.3 G34R at endogenous levels was sufficient to genocopy KDM4 triple-KO cells as determined by ChIP-seq and RNA-seq.
2018-07-08 | GSE106204 | GEO
Project description:Sequencing of paediatric gliomas has identified two common substitution mutations (K27M and G34R) in genes encoding histone H3.3. We introduced a single-copy H3.3 G34R targeted mutation in mouse ES cells and observed gains in H3K36me3 and H3K9me3 across the genome. Altered chromatin profiles correlated with enrichment of KDM4 A/B/C, a histone lysine (K9/K36) demethylase. RNA-seq of H3.3 G34R mutant showed disrupted gene expression patterns which also correlated with KDM4 enrichment. Expression of a single copy of H3.3 G34R at endogenous levels was sufficient to genocopy KDM4 triple-KO cells as determined by ChIP-seq and RNA-seq.
2018-07-08 | GSE106203 | GEO
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.
2024-01-10 | PXD041132 | Pride
Project description:Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (alpha-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n=784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.
| EGAS00001000226 | EGA