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

Oana Paun, Yu Xuan Tan, Harshil Patel, Stephanie Strohbuecker, Avinash Ghanate, Clementina Cobolli-Gigli, Miriam Llorian Sopena, Lina Gerontogianni, Robert Goldstone, Siew Lan Ang, Francois Guillemot, Cristina Dias*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)218-242
Number of pages25
JournalGenes and Development
Volume37
Issue number5-6
Early online date17 Mar 2023
DOIs
Publication statusPublished - 2023

Keywords

  • mSWI/SNF
  • neurogenesis
  • pioneer transcription factor
  • chromatin regulation
  • ASCL1
  • ChIP-seq
  • ATAC-seq
  • scRNA-seq
  • neural stem cell

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