Ascl1 Coordinately Regulates Gene Expression and the Chromatin Landscape during Neurogenesis

Abstract

SummaryThe proneural transcription factor Ascl1 coordinates gene expression in both proliferating and differentiating progenitors along the neuronal lineage. Here, we used a cellular model of neurogenesis to investigate how Ascl1 interacts with the chromatin landscape to regulate gene expression when promoting neuronal differentiation. We find that Ascl1 binding occurs mostly at distal enhancers and is associated with activation of gene transcription. Surprisingly, the accessibility of Ascl1 to its binding sites in neural stem/progenitor cells remains largely unchanged throughout their differentiation, as Ascl1 targets regions of both readily accessible and closed chromatin in proliferating cells. Moreover, binding of Ascl1 often precedes an increase in chromatin accessibility and the appearance of new regions of open chromatin, associated with de novo gene expression during differentiation. Our results reveal a function of Ascl1 in promoting chromatin accessibility during neurogenesis, linking the chromatin landscape at Ascl1 target regions with the temporal progression of its transcriptional program.

Atoh1 in sensory hair cell development: constraints and cofactors

“…The proneural bHLH transcription factor Ascl1 (closely related to Atoh1) is known to be a pioneer factor, capable of binding to nucleosomal-occluded DNA (28,29) and promoting chromatin accessibility at the regulatory regions of its targets (29). However, pioneer activity remains to be determined for Atoh1.…”

Distinct transcription factor complexes act on a permissive chromatin landscape to establish regionalized gene expression in CNS stem cells

“…Examination of chromatin accessibility by mapping DNase I hypersensitive sites (DHSs) genome wide, in a large array of stem cells and their more committed progeny, has revealed that most DHSs are cell type specific. These studies have also shown that lineage specification and maturation are characterized by a general condensation of chromatin, paralleled by a selective de novo formation of open chromatin regions (Stergachis et al 2013;LaraAstiaso et al 2014;Raposo et al 2015). Interestingly, the resulting differences in the chromatin landscape that these changes bring can accurately cluster cells according to their lineage relationships (Song et al 2011;Stergachis et al 2013).…”

Transcription-Factor-Dependent Control of Adult Hippocampal Neurogenesis

“…These results propose a model in which Mash1/Ascl1 integrates inputs from both stimulatory and inhibitory signals and converts them into a transcriptional program activating adult neural stem cells (Andersen et al 2014). The temporal progression of the transcriptional program seems to be linked to the chromatin landscape at target regions as Mash1/Ascl1 promotes chromatin accessibility during neurogenesis (Raposo et al 2015).…”