Olig1/2 Coordinately Control Oligodendrocyte Versus Interneuron Fate Acquisition in Normal Brain and H3.3G34R/V-mutant Gliomas
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ABSTRACT:
PROVIDER: PRJNA1140536 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30004039_1.fastq.gz | Fastqsanger.gz | |||
| SRR30004039_2.fastq.gz | Fastqsanger.gz | |||
| SRR30004040_1.fastq.gz | Fastqsanger.gz | |||
| SRR30004040_2.fastq.gz | Fastqsanger.gz | |||
| SRR30004041_1.fastq.gz | Fastqsanger.gz |
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Project description:Histone H3.3 glycine 34 to arginine/valine (H3.3G34R/V) mutations occur in deadly hemispheric high-grade gliomas. These tumors show exquisite regional and temporal specificity, suggesting a developmental context permissive to the effects of G34R/V mutations. Here we present the molecular landscape of G34R/V gliomas (n = 83) and show that ~50% bear activating mutations in PDGFRA, with strong selection pressure for PDGFRAMUT clones at recurrence. We show that G34R/V tumors arise in interneuron progenitors of the foetal ventral forebrain, expressing GSX2 and the DLX family of homeobox transcription factors, where terminal neuronal differentiation is impaired through aberrant G34R/V-mediated H3K27me3. Frequent co-occurrence of G34R/V & PDGFRAMUT is facilitated in this interneuron lineage-of-origin as PDGFRA forms an aberrant chromatin loop with the adjacent GSX2, hijacking its active chromatin conformation. At the single-cell level, G34R/V tumors entirely lack oligodendroglial transcriptional programs prominent in other glioma entities, and instead harbour dual neuronal and astroglial compartments. CRISPR-removal of H3.3G34R/V does not impact tumorigenicity suggesting this mutation becomes dispensable, while PDGFRAMUT are potently oncogenic regardless of G34 mutation. Collectively, our results suggest that G34R/V gliomas arise in foetal interneuron progenitors unable to terminally differentiate, enabling co-option of PDGFRA through inappropriate expression and activating mutations to promote gliogenesis and oncogenicity. Reliance on PDGFRA for oncogenesis may be of therapeutic opportunity in G34R/V glioma.
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Project description:Glial progenitor cells (GPCs) pervade the human brain. These cells express gangliosides recognized by MAb A2B5, and some but not all can generate oligodendrocytes. Since some A2B5+ GPCs express PDGFa receptor (PDGFRa), which is critical to oligodendrocyte development, we asked if PDGFRa-directed sorting might isolate oligodendrocyte-competent progenitors. We used FACS to sort PDGFRa+ cells from the second trimester fetal human forebrain, based on expression of the PDGFRa epitope CD140a. CD140a+ cells could be maintained as mitotic progenitors that could be instructed to either oligodendrocyte or astrocyte phenotype. Transplanted CD140a+ cells robustly myelinated the hypomyelinated shiverer mouse brain. Microarray confirmed that CD140a+ cells differentially expressed PDGFRA, NG2, OLIG1/2, NKX2.2 and SOX2. Some expressed CD9, thereby defining a CD140a+/CD9+ fraction of oligodendrocyte-biased progenitors. CD140a+ cells differentially expressed genes of the PTN-PTPRZ1, wnt, notch and BMP pathways, suggesting the interaction of self-renewal and fate-restricting pathways in these cells, while identifying targets for their mobilization and instruction.
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2013-01-20 | E-GEOD-42447 | biostudies-arrayexpress
Project description:Epigenetic lesions that disrupt gene regulatory elements and expression are increasingly recognized as pervasive drivers of human cancers. However, we currently lack the in vitro and in vivo models required to functionally validate such lesions and their tumorigenic impact. Here we model aberrations that arise in Isocitrate Dehydrogenase mutant (IDHmut) lower-grade gliomas, which exhibit profound DNA hypermethylation. We initially focus on a CTCF insulator downstream of the PDGFRA oncogene that is recurrently disrupted in IDHmut gliomas. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte-progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce PDGFRA, thereby increasing proliferation. In contrast, insulator disruption did not affect PDGFRA expression in neural progenitor cells (NPCs), which lack the enhancer. We also model a second recurrent epigenetic lesion in IDHmut gliomas, the methylation-dependent silencing of the CDKN2A tumor suppressor. We show that inactivation of CDKN2A/p19ARF by de novo promoter methylation or mutation drives OPC proliferation and synergizes with PDGFRA insulator loss. Finally, we use lentiviruses to coordinately inactivate the PDGFRA insulator and CDKN2A in mouse corpus callosum, resulting in low-grade gliomagenesis in vivo. Our study recapitulates recurrent epigenetic lesions in mouse models and demonstrates that combination of PDGFRA activation and CDKN2A silencing can transform OPCs in vitro and drive gliomagenesis in vivo.
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Project description:GABAergic interneuron in the cortex comprise a very heterogenous group. and it is critical to identify discrete interneuron types to understand how their contributions to behavior can be modulated by external and internal cues. However, molecular difinition of these interneuron cell groups has been difficult. Comparative analysis of different interneuron subtypes can provide us new candidate marker genes which could target more specific interneu?on cell group. Here we identify oxytocin responsive novel class of interneuron through our comparative analysis. We employed the bacTRAP strategy, which uses BAC transgenic mice expressing EGFP-tagged ribosomal protein L10a in specific cell populations, to affinity purify polysome-bound mRNAs from Nek7, Dlx1, Cort, Htr3a, Oxtr expressing cortical interneurons. We show that Oxtr expressing cells are a subtype of somatostatin positive interneurons. Three independent TRAP replicates were collected and total RNA from the immunoprecipitates or flow-through (input) whole cortex lysates were amplified and hybridized. Data were normalized with the GCRMA algorithm and replicates were averaged across conditions. We recommend filtering data to remove probe sets with normalized expression values less than 50 in at least one condition. Because the Nek7 BAC labels non-neuronal cells, we recommend to delete astrocytes and oligodendrocytes genes from the list using GSE13379 data.
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Project description:Olig1 is a bHLH transcription factor which is important for Oligodendrocyte development We used microarray profiling to assess which genes are differentially expressed in absence of Olig1 in neural stem cells.
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