CHD7 cooperates with PBAF to control multipotent neural crest formation

Abstract

SummaryHeterozygous 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 crestspecific 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.Recent studies demonstrate that unique chromatin states are associated with retained or restricted differentiation potential. 1 During organismal development, cells gradually restrict their differentiation potential to produce specialized tissues and organs. One exception is germ cell formation, which is accompanied by reacquisition of the pluripotent state. Another major developmental reprogramming event occurs in vertebrate organisms during formation of the §

Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development

“…Brg1 hydrolyzes ATP to drive the chromatin remodeling activity of the BAF complex. A recent study indirectly linked Polybromo-BAF (PBAF) (containing Brg1) to the pathogenesis of CHARGE syndrome (12), characterized by coloboma, heart defects, atresia choanae, retarded growth and development, genital hypoplasia, and ear abnormalities/deafness. CHARGE syndrome is caused by haploinsufficiency of a chromodomain chromatin-remodeling factor, ChromodomainHelicase-DNA-binding protein 7 (CHD7) (13), and includes cardiovascular defects in PAA and OFT (14).…”

“…CHARGE syndrome is caused by haploinsufficiency of a chromodomain chromatin-remodeling factor, ChromodomainHelicase-DNA-binding protein 7 (CHD7) (13), and includes cardiovascular defects in PAA and OFT (14). Although Chd7 knockdown in frog embryos causes abnormal OFT positioning, and Chd7 associates with PBAF in frog embryos (12), there is no direct evidence of the need for Brg1 in NCCs for PAA and OFT development in frogs or mice.…”

SWI/SNF Protein Component BAF250a Regulates Cardiac Progenitor Cell Differentiation by Modulating Chromatin Accessibility during Second Heart Field Development

“…The SWI/SNF complexes consist of 12 different subunits, which form BAF and PBAF complexes in mammals (7) and play a key role in various aspects of development (8). During development the ATP-dependent chromatin remodeling complexes function in a temporal-, spatial-and tissue-specific manner (7)(8)(9)(10)(11), and the variations of subunits in the complexes contribute to these specificities.…”

Prominent scapulae mimicking an inherited myopathy expands the phenotype of CHD7-related disease

“…16 It has an essential role in the formation of multipotent neural crest cells and their migration, and development into a range of head and neck structures. 17 Chick embryos have high CHD7 protein expression in the optic, otic and nasal placodes, and branchial arches, which corresponds with the structures classically affected in CHARGE syndrome. 18 The sternocleidomastoid and trapezius muscles are both innervated by the XIth cranial nerve, which has its embryological origins in the neural crest.…”