Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA391904 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5755652.fastq.gz | Fastqsanger.gz | |||
| SRR5755652_1.fastq.gz | Fastqsanger.gz | |||
| SRR5755652_2.fastq.gz | Fastqsanger.gz | |||
| SRR5755653.fastq.gz | Fastqsanger.gz | |||
| SRR5755653_1.fastq.gz | Fastqsanger.gz |
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Project description:Epigenomic analysis of Atrx deficiency in murine glioma cells of orgin [Atrx ChIP]
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Project description:The chromatin regulator ATRX is inactivated in large subsets of adult and pediatric glioma. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear. We found that Atrx loss, especially when coupled with Tp53 inactivation, promoted cell motility and modulated differentiation state in primary murine neuroepithelial progenitors, recapitulating characteristic disease phenotypes and molecular features. Moreover, Atrx deficiency induced widespread shifts in chromatin accessibility, histone composition, and gene transcription at vacant Atrx binding sites distributed across the genome. Finally, target genes mediating Atrx-deficient phenotypes in vitro exhibited similarly selective misexpression in ATRX-mutant human glioma tissues and cell lines. These findings demonstrate that, in appropriate physiological contexts, ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes.
2017-12-31 | GSE100462 | GEO
Project description:The chromatin regulator ATRX is inactivated in large subsets of adult and pediatric glioma. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear. We found that Atrx loss, especially when coupled with Tp53 inactivation, promoted cell motility and modulated differentiation state in primary murine neuroepithelial progenitors, recapitulating characteristic disease phenotypes and molecular features. Moreover, Atrx deficiency induced widespread shifts in chromatin accessibility, histone composition, and gene transcription at vacant Atrx binding sites distributed across the genome. Finally, target genes mediating Atrx-deficient phenotypes in vitro exhibited similarly selective misexpression in ATRX-mutant human glioma tissues and cell lines. These findings demonstrate that, in appropriate physiological contexts, ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes.
2017-12-31 | GSE100461 | GEO
Project description:The chromatin regulator ATRX is inactivated in large subsets of adult and pediatric glioma. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear. We found that Atrx loss, especially when coupled with Tp53 inactivation, promoted cell motility and modulated differentiation state in primary murine neuroepithelial progenitors, recapitulating characteristic disease phenotypes and molecular features. Moreover, Atrx deficiency induced widespread shifts in chromatin accessibility, histone composition, and gene transcription at vacant Atrx binding sites distributed across the genome. Finally, target genes mediating Atrx-deficient phenotypes in vitro exhibited similarly selective misexpression in ATRX-mutant human glioma tissues and cell lines. These findings demonstrate that, in appropriate physiological contexts, ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes.
2017-12-31 | GSE100464 | GEO
Project description:The chromatin regulator ATRX is inactivated in large subsets of adult and pediatric glioma. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear. We found that Atrx loss, especially when coupled with Tp53 inactivation, promoted cell motility and modulated differentiation state in primary murine neuroepithelial progenitors, recapitulating characteristic disease phenotypes and molecular features. Moreover, Atrx deficiency induced widespread shifts in chromatin accessibility, histone composition, and gene transcription at vacant Atrx binding sites distributed across the genome. Finally, target genes mediating Atrx-deficient phenotypes in vitro exhibited similarly selective misexpression in ATRX-mutant human glioma tissues and cell lines. These findings demonstrate that, in appropriate physiological contexts, ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes.
2017-12-31 | GSE100463 | GEO
Project description:Recent single-cell transcriptomic studies report that IDH-mutant gliomas share a common hierarchy of cellular phenotypes, independent of genetic subtype. However, the genetic differences between IDH-mutant glioma subtypes are prognostic, predictive of response to chemotherapy, and correlate with distinct tumor microenvironments. To reconcile these findings, we profiled 22 human IDH-mutant gliomas via single-cell assay for transposase-accessible chromatin (scATAC-seq). We determined the cell-type specific differences in transcription-factor expression and associated regulatory grammars between IDH-mutant glioma subtypes. We find that while IDH-mutant gliomas do share a common distribution of cell types, there are significant differences in the expression and targeting of transcription factors that regulate glial identity and cytokine elaboration. We knocked out the chromatin-remodeler ATRX, which suffers loss-of-function alterations in most IDH-mutant astrocytomas, in an IDH-mutant immunocompetent intracranial murine model. We find that both human ATRX-mutant gliomas and murine ATRX-knockout gliomas are more heavily infiltrated by immunosuppressive monocytic-lineage cells derived from circulation than ATRX-intact gliomas, in an IDH-mutant background. ATRX knockout in murine glioma recapitulates gene expression and open-chromatin signatures that are specific to human ATRX-mutant astrocytomas, including drivers of astrocytic lineage and immune-cell chemotaxis. ATRX knockout in murine glioma recapitulates gene expression and open chromatin signatures that are specific to human ATRX-mutant astrocytomas, including drivers of astrocytic lineage and immune-cell chemotaxis. Through single-cell cleavage under targets and tagmentation assays and meta-analysis of public data, we show that ATRX loss leads to a global depletion in CCCTC-binding factor association with DNA, gene dysregulation along associated chromatin loops, and protection from therapy-induced senescence.
2021-10-20 | GSE155430 | GEO
Project description:Mutational inactivation of α-thalassaemia/mental retardation X-linked (ATRX) represents a defining molecular feature in large subsets of adult and pediatric malignant glioma. ATRX deficiency gives rise to abnormal G-quadruplex (G4) DNA secondary structures at GC-rich regions of the genome, altering chromatin accessibility and enhancing DNA damage. Building on earlier work, we sought to assess the extent to which pharmacological G4 stabilization selectively enhances DNA damage and cell death in preclinical models of ATRX-deficient glioma. Deploying the G4 stabilizer CX-5461 in patient-derived glioma stem cells (GSCs) in vitro and in GSC murine flank and intracranial xenografts in vivo, we evaluated efficacy as both a single agent and in combination with ionizing radiation (IR), a central element of current treatment standards. CX-5461 promoted dose-sensitive lethality in ATRX-deficient GSCs relative to ATRX-intact controls. Mechanistic studies revealed that CX-5461 disrupted histone variant H3.3 deposition, enhanced replication stress and DNA damage pathways, activated p53-independent apoptosis, and induced G2/M arrest selectively in ATRX-deficient GSCs. These data were corroborated in vivo, where we notably demonstrated that combinational treatment leads to profound tumor growth delay and prolonged survival exclusively in ATRX-deficient flank tumors. In its totality, our work substantively demonstrates efficacy and defines mechanisms of action for a novel therapeutic strategy targeting ATRX-deficient malignant glioma, laying the groundwork for clinical translation.
2024-03-18 | GSE261563 | GEO