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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214700 | GEO | 2023/03/14

REPOSITORIES: GEO

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

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