Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation and is altered with age

Neural stem cells (NSCs) in the adult and aged brain are largely quiescent, and require transcriptional reprogramming to re‐enter the cell cycle. However, the mechanisms underlying these changes and how they are altered with age 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. Accessible chromatin states specific to activation or quiescence are active enhancers bound by key pro‐neurogenic and quiescence factors. 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 gene repression and associated with pro‐quiescence factors, revealing a novel mechanism that may preserve quiescence re‐entry. Furthermore, we report that in aged NSCs, chromatin regions associated with metabolic and transcriptional functions bound by key pro‐quiescence transcription factors lose accessibility, suggesting a novel mechanism of age‐associated NSC dysfunction. Together, our findings reveal how accessible chromatin states regulate the transcriptional switch between NSC quiescence and activation, and how this switch is affected with age.