Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA378791 | ENA |
REPOSITORIES: ENA
Similar Datasets
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.
2017-07-21 | GSE96088 | GEO
Project description:ASCL1 mediates neuronal differentiation of GBM stem cell (GSC) cultures. We sought to identify chromatin changes upon induced ASCL1 expression in primary human GSC cultures. In this dataset, we include ATAC-seq data obtained from GSC cultures harbouring a CRISPR-deletion of ASCL1. We assessed differential ASCL1 binding between control and GSC cultures induced to overexpress ASCL1 after 14 days of doxycycline treatment.
2017-07-13 | GSE90547 | GEO
Project description:ASCL1 mediates neuronal differentiation of GBM stem cell (GSC) cultures. We sought to identify genomic targets of ASCL1 in primary human GSC cultures. In this dataset, we include ChIP-seq data obtained from GSC cultures harbouring a CRISPR-deletion of ASCL1. We assessed differential ASCL1 binding between control and GSC cultures induced to overexpress ASCL1 after 18 hours of doxycycline treatment.
2017-07-13 | GSE87618 | GEO
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.
2013-08-13 | E-GEOD-48336 | biostudies-arrayexpress
Project description:ASCL1 mediates neuronal differentiation of GBM stem cell (GSC) cultures. We sought to identify targets of ASCL1 in primary human GSC cultures. In this dataset, we include RNA-seq data obtained from GSC cultures harbouring a CRISPR-deletion of ASCL1. We assessed differential gene expression between control and GSC cultures induced to overexpress ASCL1 after 7 days of doxycycline treatment.
2017-07-13 | GSE87617 | GEO
Project description:The proper balance of excitatory and inhibitory neurons is crucial to normal processing of somatosensory information in the dorsal spinal cord. Two neural basic helix-loop-helix transcription factors, Ascl1 and Ptf1a, are essential for generating the correct number and sub-type of neurons in multiple regions of the nervous system. M-BM- In the dorsal spinal cord, Ascl1 and Ptf1a have contrasting functions in specifying inhibitory versus excitatory neurons. To understand how Ascl1 and Ptf1a function in these processes, we identified their direct transcriptional targets genome-wide in the embryonic mouse neural tube using ChIP-Seq and RNA-Seq. We show that Ascl1 and Ptf1a regulate the specification of excitatory and inhibitory neurons in the dorsal spinal cord through direct regulation of distinct homeodomain transcription factors known for their function in neuronal sub-type specification. Besides their roles in regulating these homeodomain factors, Ascl1 and Ptf1a each function differently during neuronal development with Ascl1 directly regulating genes with roles in several steps of the neurogenic program including, Notch signaling, neuronal differentiation, axon guidance, and synapse formation. In contrast, Ptf1a directly regulates genes encoding components of the neurotransmitter machinery in inhibitory neurons, and other later aspects of neural development distinct from those regulated by Ascl1. Moreover, Ptf1a represses the excitatory neuronal fate by directly repressing several targets of Ascl1. Examination of the Ascl1 and Ptf1a bound sequences shows they are enriched for a common E-Box with a GC core and with additional motifs used by Sox, Rfx, Pou, and Homeodomain factors. Ptf1a bound sequences are uniquely enriched in an E-Box with a GA/TC core and in the binding motif for its co-factor Rbpj, providing two keys to specificity of Ptf1a binding. The direct transcriptional targets identified for Ascl1 and Ptf1a provide a molecular understanding for how they function in neuronal development, particularly as key regulators of homeodomain transcription factors required for neuronal sub-type specification. Examination of gene expression in Ascl1 and Ptf1a lineage cells in the developing neural tube.
2014-06-13 | E-GEOD-55831 | biostudies-arrayexpress
Project description:ASCL1 mediates neuronal differentiation of GBM stem cell (GSC) cultures upon Notch signalling inhibition. We sought to identify gene expression changes that were specific to ASCL1 function. In this dataset, we include RNA-seq data obtained from GSC cultures harbouring wildtype or CRISPR-deletion of ASCL1. We assessed differential gene expression between wildtype and ASCL1-knockout after treatment with gamma-secretase inhibitor for 7 days.
2017-07-13 | GSE87615 | GEO
Project description:Glioblastoma (GBM) is thought to be driven by a sub-population of cancer stem cells (CSCs) that self-renew and recapitulate tumor heterogeneity, yet remain poorly understood. Here we present a comparative epigenomic analysis of GBM CSCs that reveals widespread activation of genes normally held in check by Polycomb repressors. These activated targets include a large set of developmental transcription factors (TFs) whose coordinated activation is unique to the CSCs. We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1. We show that ASCL1 is essential for maintenance and in vivo tumorigenicity of GBM CSCs. Genomewide binding profiles for ASCL1 and the Wnt effector LEF1 provide mechanistic insight and suggest widespread interactions between the TF module and the signaling pathway. Our findings demonstrate regulatory connections between ASCL1, Wnt signaling and collaborating TFs that are essential for the maintenance and tumorigenicity of GBM CSCs. Epigenomic profiling of glioblastoma stem cells
2013-05-28 | E-GEOD-46015 | biostudies-arrayexpress
Project description:Glioblastoma (GBM) is thought to be driven by a sub-population of cancer stem cells (CSCs) that self-renew and recapitulate tumor heterogeneity, yet remain poorly understood. Here we present a comparative epigenomic analysis of GBM CSCs that reveals widespread activation of genes normally held in check by Polycomb repressors. These activated targets include a large set of developmental transcription factors (TFs) whose coordinated activation is unique to the CSCs. We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1. We show that ASCL1 is essential for maintenance and in vivo tumorigenicity of GBM CSCs. Genomewide binding profiles for ASCL1 and the Wnt effector LEF1 provide mechanistic insight and suggest widespread interactions between the TF module and the signaling pathway. Our findings demonstrate regulatory connections between ASCL1, Wnt signaling and collaborating TFs that are essential for the maintenance and tumorigenicity of GBM CSCs. Histone modification profiling for multiple marks by ChIP-Seq in untreated glioblastoma cancer stem cells, glioblastoma non-stem cells and neural stem cells
2013-05-28 | E-GEOD-46014 | biostudies-arrayexpress
Project description:The proper balance of excitatory and inhibitory neurons is crucial to normal processing of somatosensory information in the dorsal spinal cord. Two neural basic helix-loop-helix transcription factors, Ascl1 and Ptf1a, are essential for generating the correct number and sub-type of neurons in multiple regions of the nervous system. M-BM- In the dorsal spinal cord, Ascl1 and Ptf1a have contrasting functions in specifying inhibitory versus excitatory neurons. To understand how Ascl1 and Ptf1a function in these processes, we identified their direct transcriptional targets genome-wide in the embryonic mouse neural tube using ChIP-Seq and RNA-Seq. We show that Ascl1 and Ptf1a regulate the specification of excitatory and inhibitory neurons in the dorsal spinal cord through direct regulation of distinct homeodomain transcription factors known for their function in neuronal sub-type specification. Besides their roles in regulating these homeodomain factors, Ascl1 and Ptf1a each function differently during neuronal development with Ascl1 directly regulating genes with roles in several steps of the neurogenic program including, Notch signaling, neuronal differentiation, axon guidance, and synapse formation. In contrast, Ptf1a directly regulates genes encoding components of the neurotransmitter machinery in inhibitory neurons, and other later aspects of neural development distinct from those regulated by Ascl1. Moreover, Ptf1a represses the excitatory neuronal fate by directly repressing several targets of Ascl1. Examination of the Ascl1 and Ptf1a bound sequences shows they are enriched for a common E-Box with a GC core and with additional motifs used by Sox, Rfx, Pou, and Homeodomain factors. Ptf1a bound sequences are uniquely enriched in an E-Box with a GA/TC core and in the binding motif for its co-factor Rbpj, providing two keys to specificity of Ptf1a binding. The direct transcriptional targets identified for Ascl1 and Ptf1a provide a molecular understanding for how they function in neuronal development, particularly as key regulators of homeodomain transcription factors required for neuronal sub-type specification. Examination of Ascl1 and Ptf1a genome-wide binding in developing neural tube.
2014-06-13 | E-GEOD-55840 | biostudies-arrayexpress