Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation

Adult neural stem cells are largely quiescent, and require transcriptional reprogramming to re-enter the cell cycle before neurogenesis. However, mechanisms underlying the transcriptional overhaul during NSC activation remain undefined. Here, we identify the chromatin accessibility differences between primary neural stem/progenitor cells in quiescent and activated states. These distinct cellular states exhibit shared and unique chromatin profiles, both associated with gene regulation. Interestingly, accessible chromatin states specific to activation or quiescence are active enhancers bound by pro-neurogenic and quiescence factors, ASCL1 and NFI. In contrast, shared sites are enriched for core promoter elements associated with translation and metabolism. Unexpectedly, through integrated analysis, we find that many sites that become accessible during NSC activation are linked to downregulation of gene expression and associated with pro-quiescence factors, revealing a novel mechanism that may preserve quiescence re-entry. Together, our findings reveal how accessible chromatin states regulate the transcriptional switch between NSC quiescence and activation. Overall design: ATAC-seq and H3K4me3 ChIP-seq profiles of postnatal day 5 mouse neural stem/progenitor cells in activated and BMP4-induced quiescence conditions.