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ASCL1 a pioneer factor that induces subtype switching and characterizes adrenergic neuroblastoma

ABSTRACT: ASCL1 a pioneer factor that induces subtype switching and characterizes adrenergic neuroblastoma

PROVIDER: PRJNA887087 | ENA |

REPOSITORIES: ENA

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			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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ASCL1: a pioneer factor that induces subtype switching and characterizes adrenergic neuroblastoma

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

ASCL1 a pioneer factor that induces subtype switching and characterizes adrenergic neuroblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-11-21 | GSE214796 | GEO

Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at distal regulatory elements to regulate human neural differentiation

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

Single cell transcriptomes of neurally differentiated wildtype and ASCL1-KO human iPSCs, in the presence of NOTCH inhibitor DAPT [scRNA-seq]

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.

2023-03-14 | GSE214700 | GEO

Distinct associations of pioneer factor Ascl1-E12a with nucleosomes drive changes in cell fate

Project description:Understanding how pioneer transcription factors target nucleosomal DNA and initiate chromatin accessibility provides insight into the earliest events in cell fate control. We used structural, biophysical, biochemical approaches to assess how the neural pioneer factor Ascl1 heterodimerizing with E12a binds nucleosomes in vitro. The nucleosomal binding, but not free DNA binding, by Ascl1/E12 is enhanced by two types of interactions with core histones. We performed ChIP-seq and ATAC-seq to investigate how histone interaction mutants of Ascl12 (called AAA, allRs, and QA respecrively) affect its global chromatin targeting and chromatin opening.

2026-06-02 | GSE299923 | GEO

Distinct interactions between pioneer factor Ascl1/E12a and nucleosomes drive cell fate transitions [ChIP-seq]

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ASCL1 is a MYCN- and LMO1-dependent member of the adrenergic neuroblastoma core regulatory circuitry

Project description:ASCL1 is a MYCN- and LMO1-dependent member of the adrenergic neuroblastoma core regulatory circuitry

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H3K27M co-opts ASCL1 to maintain progenitor states and drive gliomagenesis

Project description:Phenotypic plasticity, a hallmark of cancer facilitated by epigenomic reprogramming, represents a significant challenge but also therapeutic opportunity for cancer treatment. How plasticity is regulated in diffuse midline gliomas (DMGs), incurable pediatric brain tumors characterized by oncogenic H3K27M histone mutations, is not understood. Here we demonstrate that H3K27M-driven plasticity requires the lineage-specific, pioneer transcription factor (TF) ASCL1. Prolonged differentiation reveals clinically relevant plasticity in DMGs, which segregate into ASCL1-high, neural progenitor cell (NPC)-like gliomaspheres and ASCL1-low, mesenchymal (MES)-like adherent subpopulations. Direct transcriptional activation by ASCL1 enables super enhancers to sustain NPC programs de-repressed by H3K27M. H3K27M loss induces an irreversible MES-like state, suppresses plasticity by abolishing the ASCL1-high state, and is largely phenocopied by loss of ASCL1. Knocking out ASCL1 in DMG lines robustly inhibited tumor growth and significantly extended survival of recipient mice. Our results suggest targeting epigenetic plasticity to suppress master TF-driven progenitor states as a general therapeutic opportunity in cancer.

2026-08-07 | GSE326427 | GEO

Distinct associations of pioneer factor Ascl1-E12a with nucleosomes drive changes in cell fate

Project description:Distinct associations of pioneer factor Ascl1-E12a with nucleosomes drive changes in cell fate

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Distinct associations of pioneer factor Ascl1-E12a with nucleosomes drive changes in cell fate

Project description:Distinct associations of pioneer factor Ascl1-E12a with nucleosomes drive changes in cell fate

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