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<p>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.</p><p></p>

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

  • 期刊论文

  • 发表日期：

    2025年8月22日

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  • Yan Luan,
  • Hanyue Zhang,
  • Yingfei Liu,
  • Jing Zhou,
  • Wen Li,
  • Kaige Ma,
  • Xiaoyan Zheng,
  • Chen Huang,
  • Xinlin Chen,
  • Haixia Lu,
  • Hui Yu,
  • Magnar Bjørås,
  • Arne Klungland,
  • Zhichao Zhang

摘要

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.