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

The dentate gyrus (DG), a crucial region of the hippocampus responsible for learning, spatial encoding, and memory formation, undergoes its main development and maturation after birth. Despite its importance, the regulatory mechanisms underlying postnatal DG development remain poorly understood. This study is aimed to investigate the role of H3 lysine 4 trimethylation (H3K4me3) and H3 lysine 27 trimethylation (H3K27me3) in the development and function of the postnatal DG. We show robust enrichment of H3K4me3 in the subgranular zone (SGZ), a primary neurogenic region, while high levels of H3K27me3 were mainly presented in granule cell layer. Enhanced H3K4me3 level facilitated proliferation and development of neonatal mouse neural stem cells (NSCs), promoted differentiation towards GABA neurons, as well as improved mouse spatial learning and memory. Enhancing H3K27me3 level exerts the opposite function, additionally promoting NSCs entry into a quiescent-like state. During the neuronal differentiation of NSCs, the integration of RNA-Seq and ChIP-Seq datasets reveals that H3K4me3 and H3K27me3 co-regulate the expression of genes essential for neural development, such as Gli1, through the formation of bivalent domains. Manipulation activation of the Shh/Gli1 pathway abolishes the effect of alterations in the levels of H3K4me3 and H3K27me3 in NSCs. Based on these findings, we propose that H3K4me3 and H3K27me3 serve as molecular “switches” to dynamically regulate NSCs proliferation and differentiation and in turn, influence the postnatal developmental progression of DG, additionally to provide potential therapeutic targets for treating diseases associated with abnormal hippocampal development.

During dentate gyrus development in neonatal mice, the active transcription mark H3K4me3 and the repressive mark H3K27me3 are co-localized at the promoter regions of essential neurodevelopmental genes, and thus forming bivalent chromatin domains in neural stem cells. These domains serve as a “molecular switch” that regulates the dynamic processes of cell proliferation and differentiation. The enhanced ratio of H3K4me3 to H3K27me3 markedly upregulates the expression related genes, thereby promoting cell proliferation and neuronal differentiation, ultimately leading to improved spatial learning and memory. Conversely, decreasing this ratio has the opposite effect.