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

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

PROVIDER: PRJNA885095 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21741200.fastq.gz	Fastqsanger.gz
	SRR21741500.fastq.gz	Fastqsanger.gz
	SRR21788600_1.fastq.gz	Fastqsanger.gz
	SRR21788600_2.fastq.gz	Fastqsanger.gz
	SRR21741201.fastq.gz	Fastqsanger.gz

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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

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

Project description: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.

| S-EPMC10111863 | biostudies-literature

Identifying the transcriptional output associated with distal regulatory elements where ASCL1 interacts with mSWI/SNF remodelers to regulate neural differentiation [RNA-seq]

Project description:We interfeered with the ASCL1-mSWI/SNF interaction: to abolish ASCL1 function, we knocked out ASCL1 in human iPSCs, while we used the BRM014 inhibitor to block the mSWI/SNF ATPase activity. We then collected RNA from WT, ASCL1 KO and BRM014-treated cells at DIV24, when ASCL1 expression is highest during neural differentiation.

2023-03-14 | GSE214382 | GEO

Identifying the genomic regions co-bound by ASCL1 and mSWI/SNF remodelers during neural differentiation [ChIP-seq]

Project description:We interfeered with the ASCL1-mSWI/SNF interaction: to abolish ASCL1 function, we knocked out ASCL1 in human iPSCs, while we used the BRM014 inhibitor to block the mSWI/SNF ATPase activity. We then performed ASCL1 ChIPseq in DIV24 WT and BRM014-treated neural cultures, and SMARCB1 ChIPseq in DIV24 WT and ASCL1 KO neural cultures, when ASCL1 expression is highest.

2023-03-14 | GSE214381 | GEO

Identifying the genomic regions where ASCL1 and mSWI/SNF remodelers are both required to regulate chromatin accessibility during neural differentiation [ATAC-seq]

Project description:We interfeered with the ASCL1-mSWI/SNF interaction: to abolish ASCL1 function, we knocked out ASCL1 in human iPSCs, while we used the BRM014 inhibitor to block the mSWI/SNF ATPase activity. We performed ATACseq in WT, ASCL1 KO, and BRM014-treated cells at DIV24, when ASCL1 expression is highest during neural differentiation.

2023-03-14 | GSE214380 | 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

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

mSWI/SNF promotes distal repression by titrating polycomb dosage

Project description:mSWI/SNF promotes distal repression by titrating polycomb dosage

| PRJNA605717 | ENA

Identifying the genomic regions co-bound by ASCL1 and mSWI/SNF remodelers during neural differentiation [ChIP-seq]

Project description:Identifying the genomic regions co-bound by ASCL1 and mSWI/SNF remodelers during neural differentiation [ChIP-seq]

| PRJNA885097 | ENA

Identifying the transcriptional output associated with distal regulatory elements where ASCL1 interacts with mSWI/SNF remodelers to regulate neural differentiation [RNA-seq]

Project description:Identifying the transcriptional output associated with distal regulatory elements where ASCL1 interacts with mSWI/SNF remodelers to regulate neural differentiation [RNA-seq]

| PRJNA885099 | ENA

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