ATPase-deficient CHD7 disease variant disrupts neural development via chromatin dysregulation

Guangfu Wang; Zhuxi Huang; Chenxi He; Ze Wang; Shuhua Dong; Ming Zhu; Fei Lan; Wenhao Zhou; Weijun Feng

doi:10.1016/j.jgg.2025.08.012

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ATPase-deficient CHD7 disease variant disrupts neural development via chromatin dysregulation

doi: 10.1016/j.jgg.2025.08.012

a. 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;
b. 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;
c. Division of Neonatology and Center for Newborn Care, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China;
d. Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China

Funds:

This research was supported by grants from National Natural Science Foundation of China (81974229 and 82171167 to W.F., 82330049 to W.Z.), Xiamen Municipal Major Project of High-Quality Development of Health and Wellness Technology Program (2024-GZL-GD06 to W.F.), National Key R&D Program of China (2022YFA0806603 to W.F.) and Science and Technology Program of Guangzhou, China (2024A04J4924 to C.H.).

Received Date: 2025-06-12
Accepted Date: 2025-08-31
Rev Recd Date: 2025-08-31

Available Online: 2025-09-08

Abstract

Abstract

Chromodomain helicase DNA binding protein 7 (CHD7), an ATP-dependent chromatin remodeler, plays versatile roles in neurodevelopment. However, the functional significance of its ATPase/nucleosome remodeling activity remains incompletely understood. Here, we generate genetically engineered mouse embryonic stem cell lines harboring either an inducible Chd7 knockout or an ATPase-deficient missense variant identified in individuals with CHD7-related disorders. Through in vitro neural induction and differentiation assays combined with mouse brain analyses, we demonstrate that CHD7 enzymatic activity is indispensable for gene regulation and neurite development. Mechanistic studies integrating transcriptomic and epigenomic profiling reveal that CHD7 enzymatic activity is essential for establishing a permissive chromatin landscape at target genes, marked by the open chromatin architecture and active histone modifications. Collectively, our findings underscore the pivotal role of CHD7 enzymatic activity in neurodevelopment and provide critical insights into the pathogenic mechanisms of CHD7 missense variants in human disease.
- CHD7,
- Missense variant,
- ATPase,
- Nucleosome remodeling activity,
- Embryonic stem cell,
- Neural differentiation

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References(45)

References

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