{"title":"Mutation of CHD7 impairs the output of neuroepithelium transition that is reversed by the inhibition of EZH2","authors":"Zhuxi Huang, Chenxi He, Guangfu Wang, Ming Zhu, Xiaoyu Tong, Yi Feng, Chenyang Zhang, Shuhua Dong, Yassin Harim, Hai-kun Liu, Wenhao Zhou, Fei Lan, Weijun Feng","doi":"10.1038/s41380-025-02990-6","DOIUrl":null,"url":null,"abstract":"<p>Haploinsufficiency of <i>CHD7</i> (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 <i>CHD7</i> in the neuroepithelium (NE) but not in the neural stem cells (NSCs) after NE transition. Loss of <i>Chd7</i> 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 <i>CHD7</i> 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 <i>CHD7</i> 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 <i>CHD7</i>-associated neurodevelopmental diseases, and identify a potential therapeutic opportunity for CHARGE syndrome.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"56 1","pages":""},"PeriodicalIF":9.6000,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41380-025-02990-6","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.