CHD7 cooperates with PBAF to control multipotent neural crest formation.
CHD7 cooperates with PBAF to control multipotent neural crest formation.
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作者：
编码CHD7（一种依赖atp的染色质重塑因子）的基因的杂合突变导致称为CHARGE综合征的复杂先天性异常星座。本研究表明，在人类和非洲爪蟾中，CHD7对于多能迁移神经嵴细胞的形成至关重要，这是一种起源于外胚层的短暂细胞群，但经过主要的基因表达重编程，获得了非常广泛的分化潜力和在全身迁移以产生骨骼、软骨、神经和心脏结构的能力。我们证明CHD7的功能对于激活神经嵴转录回路的核心成分至关重要，包括Sox9， Twist和Slug。此外，CHARGE的主要特征在爪蟾胚胎中通过下调CHD7水平或过表达其催化失活的atp酶突变体来重现。我们进一步发现，在人类多能神经嵴细胞中，CHD7与含有brg1的复合物PBAF相关，这两个因子共同占据神经嵴特异性远端SOX9增强子，以及位于TWIST1基因上游并由H3K4me1标记的新基因组元件。此外，在胚胎中，CHD7和PBAF协同作用，促进神经嵴基因表达和细胞迁移。我们的工作确定了CHD7在协调神经嵴基因表达程序中的进化保守作用，为两种不同的染色质重塑者对远端基因组元件的协同调节提供了见解，并阐明了CHARGE综合征的病理胚胎学。
Heterozygous mutations in the gene encoding CHD7, an ATP-dependent chromatin remodeler result in a complex constellation of congenital anomalies called CHARGE syndrome. Here we show that in humans and in Xenopus, CHD7 is essential for the formation of multipotent migratory neural crest cells, a transient cell population that is ectodermal in origin, but undergoes a major gene expression reprogramming to acquire a remarkably broad differentiation potential and ability to migrate throughout the body to give rise to bones, cartilages, nerves, and cardiac structures. We demonstrate that CHD7 function is essential for activation of core components of neural crest transcriptional circuitry, including Sox9, Twist and Slug. Moreover, the major features of CHARGE are recapitulated in Xenopus embryo by the downregulation of CHD7 levels or overexpression of its catalytically inactive ATP-ase mutant. We further show that in human multipotent neural crest cells, CHD7 associates with a BRG1-containing complex PBAF, and both factors co-occupy a neural crest-specific distal SOX9 enhancer, as well as a novel genomic element located upstream from TWIST1 gene and marked by H3K4me1. Furthermore, in the embryo CHD7 and PBAF act synergistically to promote neural crest gene expression and cell migration. Our work identifies an evolutionary conserved role for CHD7 in orchestrating neural crest gene expression programs, provides insights into the synergistic regulation of distal genomic elements by two distinct chromatin remodelers, and illuminates the patho-embryology of CHARGE syndrome.
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影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
4.8
作者：
Kaeser, Matthias D.;Aslanian, Aaron;Emerson, Beverly M.
通讯作者：
Emerson, Beverly M.
DOI：
10.1073/pnas.85.21.8136
发表时间：
1988-11-01
影响因子：
11.1
作者：
KENNISON, JA;TAMKUN, JW
通讯作者：
TAMKUN, JW
影响因子：
5.2
作者：
Sanlaville, Damien;Verloes, Alain
通讯作者：
Verloes, Alain
影响因子：
64.8
作者：
Lemon, B;Inouye, C;Tjian, R
通讯作者：
Tjian, R