RNA-seq analysis of ASCL1-induced neuronal differentiation in WT and MED25 knockout Glioblastoma Stem Cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA702509 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR13733800.fastq.gz | Fastqsanger.gz | |||
| SRR13733801.fastq.gz | Fastqsanger.gz | |||
| SRR13733802.fastq.gz | Fastqsanger.gz | |||
| SRR13733803.fastq.gz | Fastqsanger.gz |
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Project description:Glioblastoma stem cells were infected with lentivirus expressing a control (gRNA-AAVS1) or MED25 targeting gRNA to assess the role of MED25 in the stem cell compartment of Glioblastoma stem cells. Cells were the subjected to doxycycline-induced ASCL1 overexpression (+DOX) to induced neuronal differentiation.
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Project description:We identified a subgroup of patient-derived glioblastoma (GBM) cells that express high levels of the neurogenic transcription factor, ASCL1, which predicts response to pharmacological inhibition of the Notch signaling pathway. Treatment of ASCL1hi GBM cells with a Notch signaling inhibitor induced a change in cell fate from neoplastic to neuronal. Importantly, acquisition of the neuronal fate was accompanied by a reduction in tumorigenic potential. Loss of ASCL1 in GBM cells rendered cells no longer responsive to Notch signaling inhibition and we determined ASCL1 is required for the competency of GBM cells to undergo neuronal differentiation. Enforced ASCL1 expression directed GBM cells towards a neuronal cell fate reminiscent of terminal differentiation. RNA-seq analysis of GBM cells treated with the Notch signaling inhibitor reveals neuronal target gene activation is associated with increased stoichiometric levels of ASCL1, suggesting threshold levels of ASCL1 in GBM cells governs neuronal differentiation. We demonstrate that neoplastic cells which retain expression of key neurogenic programs can have their fates redirected towards terminal differentiation. Directed fate specification to neuronal cell types by exploiting latent neurogenic programs may be a strategy to treat a subset of GBM patients. Our findings therefore highlight the potential of differentiation therapy for a subset of molecularly defined GBMs.
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Project description:FOXO transcription factors are central regulators of longevity from worms to humans. FOXO3 – the FOXO isoform associated with exceptional human longevity – preserves adult neural stem cell pools. Here we identify FOXO3 direct targets genome-wide in primary cultures of adult neural progenitor cells (NPCs). Interestingly, FOXO3-bound sites are enriched for motifs for bHLH transcription factors and FOXO3 shares common targets with the pro-neuronal bHLH transcription factor ASCL1/MASH1 in NPCs. Analysis of the chromatin landscape reveals that FOXO3 and ASCL1 are particularly enriched at the enhancers of genes involved in neurogenic pathways. Intriguingly, FOXO3 inhibits ASCL1-dependent neurogenesis in NPCs and direct neuronal conversion in fibroblasts. FOXO3 also restrains neurogenesis in vivo. Our study identifies a genome-wide interaction between the pro-longevity transcription factor FOXO3 and the cell fate determinant ASCL1, and raises the possibility that FOXO3’s ability to restrain ASCL1-dependent neurogenesis may help preserve the neural stem cell pool. ChIP-seq profiles of two transcription factors (FOXO3 and ASCL1) and three histone marks (H3K4me1, H3K4me3 and H3K27me3) in adult mouse neural progenitor cells.
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Project description:Basic helix-loop-helix (bHLH) proneural transcription factors (TFs) Ascl1 and Neurog2 are integral to the development of the nervous system. Here, we investigated the molecular mechanisms by which Ascl1 and Neurog2 control the acquisition of generic neuronal fate and impose neuronal subtype identity. Using direct neuronal programming of embryonic stem cells, we found that Ascl1 and Neurog2 regulate distinct targets by binding to largely different sets of sites. Their divergent binding pattern is not determined by the previous chromatin state but distinguished by specific E-box enrichments which reflect the DNA sequence preference of the bHLH domain. The divergent Ascl1 and Neurog2 binding patterns result in distinct chromatin accessibility and enhancer activity landscapes that shape the binding and activity of downstream TFs during neuronal specification. Our findings suggest that proneural factors contribute to neuronal diversity by differentially altering the chromatin landscapes that shape the binding of neuronally expressed TFs.
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Project description:Basic helix-loop-helix (bHLH) proneural transcription factors (TFs) Ascl1 and Neurog2 are integral to the development of the nervous system. Here, we investigated the molecular mechanisms by which Ascl1 and Neurog2 control the acquisition of generic neuronal fate and impose neuronal subtype identity. Using direct neuronal programming of embryonic stem cells, we found that Ascl1 and Neurog2 regulate distinct targets by binding to largely different sets of sites. Their divergent binding pattern is not determined by the previous chromatin state but distinguished by specific E-box enrichments which reflect the DNA sequence preference of the bHLH domain. The divergent Ascl1 and Neurog2 binding patterns result in distinct chromatin accessibility and enhancer activity landscapes that shape the binding and activity of downstream TFs during neuronal specification. Our findings suggest that proneural factors contribute to neuronal diversity by differentially altering the chromatin landscapes that shape the binding of neuronally expressed TFs.
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