ASCL1 interacts with the mSWI/SNF at distal regulatory elements to regulate neural differentiation

Abstract

Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression. The role of neurogenic pioneer factor ASCL1 in shaping chromatin landscape in human neurogenesis remains unclear. Here we show that ASCL1 acts as a pioneer transcription factor in a transient population of progenitors. Using an in vitro ASCL1 knockout model we show it drives progenitor differentiation by cis-regulation both as a classical pioneer factor and as a non-pioneer remodeler, where ASCL1 binds permissive chromatin to induce chromatin conformation changes. We find ASCL1 directly interacts with mammalian BAF SWI/SNF chromatin remodeling complexes, essential for neurogenesis and involved in multiple neurodevelopmental disorders. ASCL1 acts as a non-pioneer chromatin remodeler to regulate gene expression at a subset of loci, requiring mBAF SWI/SNF's ATPase activity for cis-regulation of gene expression. Our findings demonstrate that ASCL1 is a key chromatin remodeler in human neurogenesis, uncovering an alternative mechanism of remodeling function dependent on partner ATPase activity.

BRG1 establishes the neuroectodermal chromatin landscape to restrict dorsal cell fates

“…However, the NFRs lost after BRG1 depletion were also enriched for motifs of many of these factors. Furthermore, many of these transcription factors have been shown to recruit BRG1 and require BRG1 to function in a variety of contexts ( 33 , 34 , 44 , 45 ). Therefore, the role of these transcription factors in directing cell fate decisions following BRG1 depletion remains unclear.…”

“…In general, conditional deletion of BAF subunits during specific stages of neural differentiation leads to pleiotropic effects on proliferation and specification of neural cell types (30,31). Throughout these processes, the BAF complex can interact with a variety of lineage-determining neural transcription factors such as SOX2, PAX6, and ASCL1 (32)(33)(34)(35).…”

NEUROG2regulates a human-specific neurodevelopmental gene regulatory program

“…Proneural transcription factors induce neural stem cells to differentiate and sustain neural lineage fidelity in two ways: they directly transactivate downstream genes and they act as pioneer transcription factors, meaning they bind target sites in ‘closed’ chromatin and unwind tightly packed nucleosomes so other neurogenic transcription factors can bind (Aydin et al, 2019; Chanda et al, 2014; Fernandez Garcia et al, 2019; Park et al, 2017; Păun et al, 2023; Raposo et al, 2015; Smith et al, 2016; Soufi et al, 2015; Wapinski et al, 2017; Wapinski et al, 2013). By altering chromatin accessibility, proneural transcription factors may be central architects of the widespread epigenomic remodeling that occurs as NPCs traverse neurodevelopment and adulthood (Yang et al, 2023).…”

“…By altering chromatin accessibility, proneural transcription factors may be central architects of the widespread epigenomic remodeling that occurs as NPCs traverse neurodevelopment and adulthood (Yang et al, 2023). Since pioneer transcription factor activity can be facilitated by interactions with chromatin remodeling complexes (Minderjahn et al, 2020) ( e.g., ASCL1 protein interacts with chromatin remodelers) (Păun et al, 2023) or by interactions with transcription factor partners (Cernilogar et al, 2019), changes to binding partners may account for differences in how murine and human NEUROG2 operate. Endogenous Ascl1 has bona fide pioneer functions in vivo (Păun et al, 2023), but Neurog2 has only been studied via over-expression (Aydin et al, 2019).…”

Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation

“…In yeast, the SWI/SNF complex is known to actively decondense chromatin, antagonize chromatin-mediated transcriptional repression, and act as gene transcription activators 30,31 . In mammals, BAF complexes work in concert with many transcription factors to promote chromatin accessibility and transcription 32 . They are enriched at promoters and enhancers, where they are implicated in promoter-enhancer interactions, enhancer maintenance, and activation of lineage-specific enhancers [33][34][35][36] .…”