Inverse and dynamic levels of H3K4me3 and H3K27me3 regulate mouse postnatal dentate gyrus development

Dentate gyrus (DG) is part of the hippocampus formation and primarily mature after birth. It undergoes rapid early development followed by a protracted developmental process and is crucial for learning and memory. This unique developmental trajectory challenge mechanistic studies and our understanding of its regulatory processes are limited. Our study demonstrates that histone H3K4me3 and H3K27me3 are essential in regulating DG development. H3K4me3, which is enriched in the subgranular zone, promotes the proliferation and differentiation of neural stem cells (NSCs) into GABAergic neurons, thereby enhancing spatial learning and memory in mice. Conversely, enhancing H3K27me3 levels exert the opposite effect, additionally driving NSCs into a quiescent-like state. Furthermore, we show that H3K4me3 and H3K27me3 co-regulate the expression of genes essential for neural development, such as GLI1, through the formation of bivalent domains. These findings indicate that H3K4me3 and H3K27me3 act as molecular “switches” governing DG development.