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Mutation of CHD7 impairs the output of neuroepithelium transition that is reversed by the inhibition of EZH2

Molecular Psychiatry volume 30, pages 4094–4109 (2025)Cite this article

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Abstract

Haploinsufficiency of CHD7 (Chromo-Helicase-DNA binding protein 7) causes a severe congenital disease CHARGE syndrome. Brain anomaly such as microcephaly and olfactory bulb agenesis seen in CHARGE patients have not been mimicked in previous animal models. Here, we uncover an indispensable function of CHD7 in the neuroepithelium (NE) but not in the neural stem cells (NSCs) after NE transition. Loss of Chd7 in mouse NE resulted in CHARGE-like brain anomalies due to reduced proliferation and differentiation of neural stem and progenitor cells, which were recapitulated in CHD7 KO human forebrain organoids. Mechanistically, we find that CHD7 activates neural transcription factors by removing the repressive histone mark H3K27me3 and promoting chromatin accessibility. Importantly, neurodevelopmental defects caused by CHD7 loss in human brain organoids and mice were ameliorated by the inhibition of H3K27me3 methyltransferase EZH2. Altogether, by implementing appropriate experimental models, we uncover the pathogenesis of CHD7-associated neurodevelopmental diseases, and identify a potential therapeutic opportunity for CHARGE syndrome.

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Fig. 1: Ablation of Chd7 in mouse NE leads to microcephaly and OB hypoplasia.
Fig. 2: Loss of CHD7 impairs neuroepithelium expansion in human brain organoids.
Fig. 3: CHD7 is required for the activation of neural TFs in NE by maintaining an open chromatin structure.
Fig. 4: EZH2 inhibition leads to PAX6 reactivation and rescues neurodevelopmental defects in CHD7 KO brain organoids.
Fig. 5: Inhibition of EZH2 during the NE stage rescues OB development, midline hypoplasia, and GnRH migration in Chd7Sox1-cKO mice.
Fig. 6: CHD7 binds to its target genes and interacts with H3K27me3 demethylases and H3K4 methyltransferase complex.

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Data availability

All sequencing data are deposited in GSE255572 (reviewer token: mluhgmwmtjurjor).

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Acknowledgements

We thank Nil Aygün and Anna Neuerburg for technical support. We acknowledge Dr. Ning Sun for providing reagents. The graphical cartoons were from BioRender.

Funding

This study was supported by National Key R&D Program of China (2022YFA0806603; 2021YFA1300100); National Natural Science Foundation of China (81974229; 82171167; 31925010; 32300461; 82330049); Shanghai Municipal Science and Technology Major Project (2017SHZDZX01) and the CHARGE Syndrome Foundation Scientific Research Grant (2017) and China National Postdoctoral Program for Innovative Talents (BX20230098).

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Author notes

  1. These authors contributed equally: Zhuxi Huang, Chenxi He, Guangfu Wang.

Authors and Affiliations

  1. Institute of Pediatrics, Children’s Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China

    Zhuxi Huang, Guangfu Wang, Ming Zhu, Chenyang Zhang, Shuhua Dong & Weijun Feng

  2. Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China

    Chenxi He & Fei Lan

  3. State Key Laboratory of Medical Neurobiology, Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Institutes of Brain Science, Brain Science Collaborative Innovation Center, Fudan Institutes of Integrative Medicine, Fudan University, Shanghai, 200032, China

    Xiaoyu Tong & Yi Feng

  4. Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, 69120, Germany

    Yassin Harim & Hai-kun Liu

  5. Division of Neonatology and Center for Newborn Care, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China

    Wenhao Zhou

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Contributions

WF, FL, WZ and HKL conceived and designed the study. ZH performed murine experiments with assistant from MZ, SD and YH. GW, MZ and ZH performed brain organoid experiments. CH performed epigenomic assays and bioinformatical analysis with assistant from GW. XT, CZ performed tissue clearing, imaging and analysis with the supervision from YF. WF and FL supervised the project, prepared figures and wrote the manuscript.

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Correspondence to Fei Lan or Weijun Feng.

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Competing interests

Fei Lan is a scientific co-founder and stockholder of Active Motif Shanghai, Inc. and Alternative Bio, Inc. All other authors declare no competing interests.

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Huang, Z., He, C., Wang, G. et al. Mutation of CHD7 impairs the output of neuroepithelium transition that is reversed by the inhibition of EZH2. Mol Psychiatry 30, 4094–4109 (2025). https://doi.org/10.1038/s41380-025-02990-6

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