ASCL1 a pioneer factor that induces subtype switching and characterizes adrenergic neuroblastoma
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ABSTRACT:
PROVIDER: PRJNA887087 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21802800.fastq.gz | Fastqsanger.gz | |||
| SRR21802900.fastq.gz | Fastqsanger.gz | |||
| SRR21803000_1.fastq.gz | Fastqsanger.gz | |||
| SRR21803000_2.fastq.gz | Fastqsanger.gz | |||
| SRR21802801.fastq.gz | Fastqsanger.gz |
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Project description:Neuroblastoma is an embryonic malignancy originating from early nerve cells. Neuroblastoma retains plasticity, interconverting between the mesenchymal (MES) and adrenergic (ADRN) states, which are controlled by different sets of transcription factors forming the core regulatory circuit (CRC). However, their functional roles and cooperative mechanisms in neuroblastoma pathogenesis are poorly understood. Here, we demonstrate that overexpression of ASCL1 in MES neuroblastoma cells opens closed chromatin at the promoters of key ADRN genes, accompanied by epigenetic activation and establishment of enhancer-promoter interactions, thereby initiating subtype switching. ASCL1 inhibits the TGFb-SMAD2/3 pathway but activates the BMP-SMAD1-ID3/4 pathway, serving as negative feedback to balance the function of ASCL1-TCF12 dimers. ASCL1 and other ADRN CRC members potentiate each other’s activity, increasing the expression of the original targets and inducing a new set of genes, thereby promoting conversion to ADRN neuroblastoma. Thus, via its pioneer factor function, ASCL1 serves as a master regulator that characterizes ADRN neuroblastoma.
2023-12-08 | PXD037670 | Pride
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2023-11-21 | GSE214796 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression, though mechanisms through which pioneer transcription factors remodel chromatin remain unclear. Here, using single-cell transcriptomics, we show that endogenous expression of neurogenic transcription factor ASCL1, considered a classical pioneer factor, defines a transient population of progenitors in human neural differentiation. Testing ASCL1’s pioneer function using a knockout model to define the unbound state, we found that endogenous expression of ASCL1 drives progenitor differentiation by cis-regulation both as a classical pioneer factor and as a nonpioneer remodeler, where ASCL1 binds permissive chromatin to induce chromatin conformation changes. ASCL1 interacts with BAF SWI/SNF chromatin remodeling complexes, primarily at targets where it acts as a nonpioneer factor, and we provide evidence for codependent DNA binding and remodeling at a subset of ASCL1 and SWI/SNF cotargets. Our findings provide new insights into ASCL1 function regulating activation of long-range regulatory elements in human neurogenesis and uncover a novel mechanism of its chromatin remodeling function codependent on partner ATPase activity.
2023-03-14 | GSE214383 | GEO
Project description:The roles of neurogenic pioneer transcription factors and chromatin remodelers have been characterized in that process in developing animal models and cancers. However how these factors interact with each other to regulate cell state transitions in human neurogenesis remains unclear. Here we investigated the activity of the pioneer proneural factor ASCL1 in an in vitro model of human neurogenesis. We found that ASCL1 expression characterizes a transitional state from cycling neural progenitor to post-mitotic neuron, and ASCL1 knockout impedes progenitor neuronal differentiation. ASCL1 binds to genomic targets to regulate loci promoting differentiation by different mechanisms. Acting as a classical pioneer transcription factor, its binding to compacted chromatin is required to induce transcriptional activity. At other loci, it acts as a non-pioneer chromatin remodeler, accessing permissive chromatin to further increase chromatin accessibility. We show that ASCL1 interacts with ATPase-active BAF mSWI/SNF chromatin remodelers at cis-regulatory elements, altering the chromatin regulatory landscape at a subset of target genes. This cooperative function is predominant at sites of non-pioneer chromatin remodeler function where ASCL1 requires mSWI/SNF for DNA binding while ASCL1 classical pioneer activity does not involve significant mSWI/SNF binding. Our work establishes novel roles for ASCL1 and for an interaction with mSWI/SNF in regulating epigenetic states in human neurogenesis.
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Project description:ASCL1 is a MYCN- and LMO1-dependent member of the adrenergic neuroblastoma core regulatory circuitry
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Project description:Here we performed a ChIP-seq experiment on a sample of adherent cultures of mouse neural stem cells (NS5 cell line) under normal growth conditions and upon short term activation (30 minutes) of an inducible version of the proneural factor Mash1/Ascl1 (Ascl1-ERT2). This resulted in the generation of a genome-wide map of Ascl1 binding to chromatin.
2015-02-16 | E-MTAB-2384 | biostudies-arrayexpress
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:In castration-resistant prostate cancer, lineage plasticity mediates resistance to androgen receptor pathway inhibitors (ARPIs) and progression from adenocarcinoma to neuroendocrine prostate cancer (NEPC), a highly aggressive and poorly understood subtype. ASCL1 has emerged as a central regulator of the NEPC phenotype, driving neuroendocrine differentiation. However, ASCL1’s influence on neuronal lineage switching and maturation, as well as its partners in NEPC, remain largely unknown. Here, we provided insights into ASCL1’s cistrome reprogramming in ARPI-induced NEPC versus terminal NEPC and showed that ASCL1 binding pattern tailors the subsequent expression of transcription factor combinations that underlie discrete terminal NEPC identity. We identified FOXA2 as a major co-factor of ASCL1 in terminal NEPC that it is highly expressed in ASCL1-driven NEPC. FOXA2 and ASCL1 interact and work in concert to orchestrate terminal neuronal differentiation in prostate cancer, and regulate key neuroendocrine-associated genes including PROX1. Our findings provide insights into the molecular conduit underlying the interplay between different lineage determinant transcription factors to support the neuroendocrine identity in prostate cancer.
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Project description:In castration-resistant prostate cancer, lineage plasticity mediates resistance to androgen receptor pathway inhibitors (ARPIs) and progression from adenocarcinoma to neuroendocrine prostate cancer (NEPC), a highly aggressive and poorly understood subtype. ASCL1 has emerged as a central regulator of the NEPC phenotype, driving neuroendocrine differentiation. However, ASCL1’s influence on neuronal lineage switching and maturation, as well as its partners in NEPC, remain largely unknown. Here, we provided insights into ASCL1’s cistrome reprogramming in ARPI-induced NEPC versus terminal NEPC and showed that ASCL1 binding pattern tailors the subsequent expression of transcription factor combinations that underlie discrete terminal NEPC identity. We identified FOXA2 as a major co-factor of ASCL1 in terminal NEPC that it is highly expressed in ASCL1-driven NEPC. FOXA2 and ASCL1 interact and work in concert to orchestrate terminal neuronal differentiation in prostate cancer, and regulate key neuroendocrine-associated genes including PROX1. Our findings provide insights into the molecular conduit underlying the interplay between different lineage determinant transcription factors to support the neuroendocrine identity in prostate cancer.
2024-10-23 | GSE273956 | GEO
Project description:The pediatric extra-cranial tumor neuroblastoma displays a low mutational burden while recurrent copy number alterations are present in most high-risk cases. We identify SOX11 as a dependency transcription factor in adrenergic neuroblastoma based on recurrent chromosome 2p focal gains and amplifications, specific expression in the normal sympatho-adrenal lineage and adrenergic neuroblastoma, regulation by multiple adrenergic specific (super-)enhancers and strong dependency on high SOX11 expression in adrenergic neuroblastomas. SOX11 regulated direct targets include genes implicated in epigenetic control, cytoskeleton and neurodevelopment. Most notably, SOX11 controls chromatin regulatory complexes, including 10 SWI/SNF core components among which SMARCC1, SMARCA4/BRG1 and ARID1A. Additionally, the histone deacetylase HDAC2, PRC1 complex component CBX2, chromatin-modifying enzyme KDM1A/LSD1 and pioneer factor c-MYB are regulated by SOX11. Finally, SOX11 is identified as a core transcription factor of the core regulatory circuitry (CRC) in adrenergic high-risk neuroblastoma with a potential role as epigenetic master regulator upstream of the CRC.
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