Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature. 2010 Feb 18;463(7283):958-62. doi: 10.1038/nature08733. Epub 2010 Feb 3.
Heterozygous mutations in the gene encoding the CHD (chromodomain helicase DNA-binding domain) member CHD7, an ATP-dependent chromatin remodeller homologous to the Drosophila trithorax-group protein Kismet, result in a complex constellation of congenital anomalies called CHARGE syndrome, which is a sporadic, autosomal dominant disorder characterized by malformations of the craniofacial structures, peripheral nervous system, ears, eyes and heart. Although it was postulated 25 years ago that CHARGE syndrome results from the abnormal development of the neural crest, this hypothesis remained untested. Here we show that, in both humans and Xenopus, CHD7 is essential for the formation of multipotent migratory neural crest (NC), a transient cell population that is ectodermal in origin but undergoes a major transcriptional reprogramming event to acquire a remarkably broad differentiation potential and ability to migrate throughout the body, giving rise to craniofacial bones and cartilages, the peripheral nervous system, pigmentation and cardiac structures. We demonstrate that CHD7 is essential for activation of the NC transcriptional circuitry, including Sox9, Twist and Slug. In Xenopus embryos, knockdown of Chd7 or overexpression of its catalytically inactive form recapitulates all major features of CHARGE syndrome. In human NC cells CHD7 associates with PBAF (polybromo- and BRG1-associated factor-containing complex) and both remodellers occupy a NC-specific distal SOX9 enhancer and a conserved genomic element located upstream of the TWIST1 gene. Consistently, during embryogenesis CHD7 and PBAF cooperate to promote NC gene expression and cell migration. Our work identifies an evolutionarily conserved role for CHD7 in orchestrating NC gene expression programs, provides insights into the synergistic control of distal elements by chromatin remodellers, illuminates the patho-embryology of CHARGE syndrome, and suggests a broader function for CHD7 in the regulation of cell motility.
CHD（染色质螺旋酶结构域结合结构域）成员 CHD7 基因的杂合突变导致一种称为 CHARGE 综合征的先天性异常的复杂综合征，该基因编码 ATP 依赖性染色质重塑剂，与果蝇 trithorax 组蛋白 Kismet 同源，这是一种散发性常染色体显性疾病，其特征为颅面结构、周围神经系统、耳朵、眼睛和心脏的畸形。尽管 25 年前就有人推测 CHARGE 综合征是由于神经嵴的异常发育引起的，但这一假说一直未得到验证。在这里，我们表明，在人和非洲爪蟾中，CHD7 对于多能迁移性神经嵴（NC）的形成是必不可少的，NC 是一种短暂的细胞群体，起源于外胚层，但经历了主要的转录重编程事件，获得了广泛的分化潜能和在整个身体中迁移的能力，从而产生颅面骨骼和软骨、周围神经系统、色素沉着和心脏结构。我们证明 CHD7 对于 NC 转录电路的激活是必不可少的，包括 Sox9、Twist 和 Slug。在非洲爪蟾胚胎中，Chd7 的敲低或其催化失活形式的过表达重现了 CHARGE 综合征的所有主要特征。在人类 NC 细胞中，CHD7 与 PBAF（多溴和 BRG1 相关因子包含的复合物）相关，并且这两种重塑因子都占据 NC 特异性的远端 SOX9 增强子和位于 TWIST1 基因上游的保守基因组元件。一致地，在胚胎发生过程中，CHD7 和 PBAF 合作促进 NC 基因表达和细胞迁移。我们的工作确定了 CHD7 在协调 NC 基因表达程序中的一个进化保守作用，提供了关于染色质重塑因子对远端元件协同控制的见解，阐明了 CHARGE 综合征的病理胚胎学，并提示 CHD7 在调节细胞迁移性方面具有更广泛的功能。
