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

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.