Author:
Chai MuhChyi,Sanosaka Tsukasa,Okuno Hironobu,Zhou Zhi,Koya Ikuko,Banno Satoe,Andoh-Noda Tomoko,Tabata Yoshikuni,Shimamura Rieko,Hayashi Tetsutaro,Ebisawa Masashi,Sasagawa Yohei,Nikaido Itoshi,Okano Hideyuki,Kohyama Jun
Abstract
Multiple congenital disorders often present complex phenotypes, but how the mutation of individual genetic factors can lead to multiple defects remains poorly understood. In the present study, we used human neuroepithelial (NE) cells and CHARGE patient-derived cells as an in vitro model system to identify the function of chromodomain helicase DNA-binding 7 (CHD7) in NE–neural crest bifurcation, thus revealing an etiological link between the central nervous system (CNS) and craniofacial anomalies observed in CHARGE syndrome. We found that CHD7 is required for epigenetic activation of superenhancers and CNS-specific enhancers, which support the maintenance of the NE and CNS lineage identities. Furthermore, we found that BRN2 and SOX21 are downstream effectors of CHD7, which shapes cellular identities by enhancing a CNS-specific cellular program and indirectly repressing non-CNS-specific cellular programs. Based on our results, CHD7, through its interactions with superenhancer elements, acts as a regulatory hub in the orchestration of the spatiotemporal dynamics of transcription factors to regulate NE and CNS lineage identities.
Funder
Japan Society for the Promotion of Science KAKENHI
Eisai Co., Ltd.
Research Project for Practical Application of Regenerative Medicine
Japan Agency for Medical Research and Development
Research Center Network for Realization of Regenerative Medicine
Japan Sciences and Technology Agency
AMED
Platform Project for Supporting Drug Discovery and Life Science Research
Platform for Drug Discovery, Informatics, and Structural Life Science
Ministry of Education, Culture, Sports, Science and Technology
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
27 articles.
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