CHD7 cooperates with PBAF to control multipotent neural crest formation

摘要

“CHARGE综合症”是一种罕见的先天性症候，rn其特征是颅面结构、周围神经系统、耳朵、眼rn睛和心脏畸形。它是由为CHD7(一种依赖于rnATP的染色质重塑蛋白)编码的基因所发生的杂rn合突变引起的。人们在25年前假设，“CHARGErn综合症”由神经冠的异常发育导致。这一假设rn一直未能得到验证，但现在Bajpai等人发现，rnCHD7是多能迁移性神经冠的形成所必需的，rn是激发神经冠转录回路所必需的。另外，CHD7rn还被发现与另一染色质重塑复合物PBAF共同rn作用，来促进神经冠基因表达和细胞迁移。%Heterozygous mutations in the gene encoding the CHD (chromo-domain 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 untested5. 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 over-expression 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 embryo-genesis 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.