SETDB1 ensures the continuity of embryonic to adult neural stem cells through metabolic alterations in the dentate gyrus.

Embryonic neural progenitors give rise to adult neural stem cells (aNSCs), which share transcriptomic similarities with astrocytes while sustaining neurogenesis in the adult brain. How embryonic neural progenitors transit into aNSCs while preventing astrocyte fate to maintain the aNSC pool remains unclear. Here, we found that the Setdb1-mediated metabolic state is essential for the transition from embryonic neural progenitors to aNSCs. Loss of the histone methyltransferase SETDB1 during dentate gyrus development leads to increased astrocyte production at the expense of aNSCs and ultimately constraining neurogenesis. Single-cell RNA sequencing reveals a specific metabolic alteration following Setdb1 loss, notably implicating the cytochrome c oxidase, subunit 6b2 (Cox6b2)-a component of the mitochondrial complex-as a key target of SETDB1. COX6B2 modulates oxidative phosphorylation (OXPHOS) to control aNSC fate over astrocyte differentiation. Elevated Cox6b2 levels promote astrocyte fate during dentate gyrus development. Thus, our findings reveal a mechanism underlying the continuity of neural progenitors to generate aNSC enabling the production of new neurons in the adult brain, highlighting the potential therapeutic strategies for transforming astrocytes into neurons via aNSCs.