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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Oct 20, 2021 |
| Title |
A single-cell epigenetic atlas of human IDH-mutant glioma |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
We profiled specimens from 22 grade-II/III IDH-mutant untreated human gliomas via single-cell assay for transposase-accessible chromatin (scATAC-seq). We profiled murine IDH1R132H+/ATRX-KO and IDH1R132H/ATRX-intact gliomas via scATAC-seq, snRNA-seq, and anti-CTCF snCUT&Tag.
*** Raw data not available due to privacy concerns.
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| Contributor(s) |
Babikir H, Wang L, Shamardani K, Catalan F, Sudhir S, Aghi MK, Raleigh D, Phillips JJ, Diaz AA |
| Citation(s) |
34763709 |
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| Submission date |
Jul 30, 2020 |
| Last update date |
May 16, 2022 |
| Contact name |
Aaron Diaz |
| E-mail(s) |
aaron.diaz@ucsf.edu
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| Organization name |
University of California, San Francisco
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| Department |
Neurological Surgery
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| Lab |
Diaz Lab
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| Street address |
1450 3rd St
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| City |
San Francisco |
| State/province |
CA |
| ZIP/Postal code |
94158 |
| Country |
USA |
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| Platforms (2) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (23)
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| Relations |
| BioProject |
PRJNA649750 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE155430_RAW.tar |
270.1 Mb |
(http)(custom) |
TAR (of BED, MTX, TSV, TXT) |
| Processed data provided as supplementary file |
| Raw data not provided for this record |
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