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

Cell Death & Differentiation volume 33, pages 219–235 (2026)Cite this article

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Abstract

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.

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Fig. 1: The levels and distribution of H3K4me3 and H3K27me3 exhibit significant dynamic changes during dentate gyrus development.
Fig. 2: H3K4me3 and H3K27me3 participate in regulating the neuronal differentiation of cultured neonatal mouse hippocampal NSCs.
Fig. 3: H3K4me3 and H3K27me3 play crucial roles in the proliferation of cultured neonatal mouse hippocampal NSCs.
Fig. 4: H3K4me3 and H3K27me3 affect NSCs proliferation and neuronal differentiation during the mouse dental gyrus development.
Fig. 5: Alteration in the level of H3K4me3 and H3K27me3 affect mouse behaviors.
Fig. 6: H3K4me3 and H3K27me3 regulate the expression of neurodevelopmental genes by forming bivalent domains.
Fig. 7: Shh/Gli1 pathway is closely involved in regulating the effect of H3K4me3 and H3K27me3 in mouse hippocampal NSCs.

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Data availability

The ChIP-seq and RNA-seq data have been deposited to NCBI database with the BioProject ID PRJNA 1179734 and are publicly available as of the date of publication. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (No.81901156, 82271200, 82400174, 82171308); Research Council of Norway through its Centers of Excellence scheme (332713).

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  1. These authors contributed equally: Yan Luan, Hanyue Zhang.

Authors and Affiliations

  1. Department of Pediatric Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

    Yan Luan, Hanyue Zhang, Hui Yu & Zhichao Zhang

  2. Institute of Neurobiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China

    Yan Luan, Hanyue Zhang, Yingfei Liu, Kaige Ma, Xinlin Chen, Haixia Lu & Zhichao Zhang

  3. Department of Pathology, Shaanxi Provincial People’s Hospital, Xi’an, China

    Yan Luan

  4. Department of Hematology, Shaanxi Provincial People’s Hospital, Xi’an, China

    Yingfei Liu

  5. Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China

    Jing Zhou, Wen Li & Chen Huang

  6. Department of Hematology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

    Xiaoyan Zheng

  7. Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway

    Magnar Bjørås & Arne Klungland

  8. CRESCO, Centre for Embryology and Healthy Development, Department of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway

    Magnar Bjørås & Arne Klungland

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Contributions

YL and HZ performed all experiments and data processing. YL and HY performed cell culture and immunostaining. WL performed immunostaining and confocal imaging. JZ performed ChIP experiments. KM and XZ performed animal behavior analysis. CH, XC, and HL helped designed and refine the experiments. AK and ZZ conceived the project and designed the experiments, with assistance from MB. ZZ wrote the manuscript, with input and editing from MB and AK.

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Correspondence to Arne Klungland or Zhichao Zhang.

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The authors declare no competing interests.

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All methods were performed in accordance with the relevant guidelines and regulations. Mouse experiments were approved by the Institutional Animal Care and Use Committee of Xi’an Jiaotong University (No. XJTUAE2022-445). Mice were housed under standard conditions, which entailed housing in facilities with a 12-h light/dark cycle, ad libitum access to food and water, and a temperature range of 20–24 °C. Stringent measures were taken to mitigate animal suffering and reduce the overall number of animals utilized. We thank the Laboratory Animal Center at Xi’an Jiaotong University for their assistance with housing and breeding experimental mice. This study does not directly involve human subjects or human data that requires ethical approval.

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Luan, Y., Zhang, H., Liu, Y. et al. Inverse and dynamic levels of H3K4me3 and H3K27me3 regulate mouse postnatal dental gyrus development. Cell Death Differ 33, 219–235 (2026). https://doi.org/10.1038/s41418-025-01563-y

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