TY  - JOUR
AU  - Huang, Zhuxi
AU  - He, Chenxi
AU  - Wang, Guangfu
AU  - Zhu, Ming
AU  - Tong, Xiaoyu
AU  - Feng, Yi
AU  - Zhang, Chenyang
AU  - Dong, Shuhua
AU  - Harim, Yassin
AU  - Liu, Haikun
AU  - Zhou, Wenhao
AU  - Lan, Fei
AU  - Feng, Weijun
TI  - Mutation of CHD7 impairs the output of neuroepithelium transition that is reversed by the inhibition of EZH2.
JO  - Molecular psychiatry
VL  - 30
IS  - 9
SN  - 1359-4184
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-00688
SP  - 4094-4109
PY  - 2025
N1  - DKFZ-ZMBH Alliance /2025 Sep;30(9):4094-4109
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40164694
DO  - DOI:10.1038/s41380-025-02990-6
UR  - https://inrepo02.dkfz.de/record/300226
ER  -