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Genes Dev. 2018 Jan 15;32(2):165-180. doi: 10.1101/gad.301887.117. Epub 2018 Feb 9.

Chromatin remodeler CHD7 regulates the stem cell identity of human neural progenitors.

Author information

1
Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
2
Gene Regulation Research, Nara Institute of Science and Technology, Ikoma, Nara 630-0101, Japan.
3
E-WAY Research Laboratory, Discovery, Medicine Creation, Neurology Business Group, Tsukuba, Ibaraki 300-2635, Japan.
4
Bioinformatics Research Unit, Advanced Center for Computing and Communication, RIKEN, Wako, Saitama 351-0198, Japan.
5
Single-Cell Omics Research Unit, RIKEN Center for Developmental Biology, Wako, Saitama 351-0198, Japan.
#
Contributed equally

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.

KEYWORDS:

CHARGE syndrome; CHD7; ChIP-seq; neural crest; neural progenitors; superenhancers

PMID:
29440260
PMCID:
PMC5830929
DOI:
10.1101/gad.301887.117
[Indexed for MEDLINE]
Free PMC Article

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