Distinct epigenetic and metabolic states reflect the regional identity of adult neural stem cells and prime their fate

Abstract Neural stem/progenitor cells (NSPCs) in the adult mouse brain reside in distinct niches, including the dentate gyrus (DG) and subventricular zone (SVZ). The contribution of cell intrinsic versus extrinsic factors to distinct fates of NSPCs and their neuronal progeny remains largely unknown. We here show that DG- and SVZ-derived NSPCs retain niche-specific chromatin accessibility states that predict neuronal subtype specification. Furthermore, metabolic profiling and gene expression analyses comparing DG- and SVZ-derived NSPCs revealed differences in carnitine synthesis pathways and lipid metabolism. Supplementation with carnitine or S-adenosylmethionine (SAM) induced chromatin remodeling via histone modifications, indicating that a metabolic-epigenetic cross-talk determines regional neuronal identity. Our findings show that NSPCs are intrinsically programmed by chromatin and metabolic states, and that metabolic interventions alter epigenetic landscapes and fate potential.