A single-cell epigenetic atlas of human IDH-mutant glioma
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PROVIDER: PRJNA649750 | ENA |
REPOSITORIES: ENA
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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:RNA-sequencing for myeloid inflammation-related genes was conducted on primary tumor samples from patients with IDH-wildtype glioblastoma (GBM) and grade 4 IDH-mutant astrocytoma (G4IMA). In addition, the IDH-wildtype murine glioma cell line GL261 and a strain of IDH-mutant GL261 were also sequenced using the murine counterpart of the RNA-sequencing myeloid innate immunity panel.
2024-05-29 | GSE268118 | GEO
Project description:Single-Cell Sequencing of IDH-Mutant Glioma
| PRJNA1125010 | ENA
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-20 | GSE324694 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-20 | GSE324481 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-23 | GSE324860 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-23 | GSE327580 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-23 | GSE326221 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-20 | GSE324714 | GEO
Project description:Recent single-cell RNA-sequencing studies have identified a hierarchy of cell types that is common to all isocitrate dehydrogenase (IDH) -mutant gliomas. This finding is somewhat paradoxical since the genetic differences between IDH-mutant astrocytomas and IDH-mutant oligodendrogliomas are prognostic, predictive of therapeutic response, and correlated with differences in immune infiltrates. To integrate these disparate findings, we constructed a single-cell atlas of 28 human IDH-mutant primary untreated grade-II/III gliomas.
| EGAS00001004523 | EGA