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染色质重塑因子 CHD7 调控人神经祖细胞的干细胞特性。

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

机构信息

Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.

Gene Regulation Research, Nara Institute of Science and Technology, Ikoma, Nara 630-0101, Japan.

出版信息

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

DOI:10.1101/gad.301887.117
PMID:29440260
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5830929/
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.

摘要

多种先天性疾病常表现出复杂的表型，但单个遗传因素的突变如何导致多种缺陷仍知之甚少。在本研究中，我们使用人神经上皮（NE）细胞和 CHARGE 患者来源的细胞作为体外模型系统，以确定染色质结构域螺旋酶 DNA 结合蛋白 7（CHD7）在 NE-神经嵴分叉中的功能，从而揭示 CHARGE 综合征中观察到的中枢神经系统（CNS）和颅面异常之间的病因联系。我们发现 CHD7 对于超增强子和 CNS 特异性增强子的表观遗传激活是必需的，这支持了 NE 和 CNS 谱系身份的维持。此外，我们发现 BRN2 和 SOX21 是 CHD7 的下游效应物，通过增强 CNS 特异性细胞程序并间接抑制非 CNS 特异性细胞程序来塑造细胞身份。基于我们的结果，CHD7 通过与超增强子元件的相互作用，作为调节转录因子时空动力学的调控中枢，以调节 NE 和 CNS 谱系身份。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0814/5830929/9428736fe4a4/165f06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0814/5830929/9a2f9fa20313/165f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0814/5830929/facc6dc34dec/165f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0814/5830929/bd19f9552a35/165f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0814/5830929/66687dd69274/165f04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0814/5830929/9246011c7aeb/165f05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0814/5830929/9428736fe4a4/165f06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0814/5830929/9a2f9fa20313/165f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0814/5830929/facc6dc34dec/165f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0814/5830929/bd19f9552a35/165f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0814/5830929/66687dd69274/165f04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0814/5830929/9246011c7aeb/165f05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0814/5830929/9428736fe4a4/165f06.jpg

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