Article

Bajpai, R. et al. CHD7 cooperates with PBAF to control multipotent neural crest formation. Nature 463, 958-962

Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature (Impact Factor: 41.46). 02/2010; 463(7283):958-62. DOI: 10.1038/nature08733
Source: PubMed

ABSTRACT

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.

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Available from: Ching-Pin Chang, Oct 17, 2014
    • "We further note that these studies illustrate that different animal model systems can often complement each other in analyzing the consequences of a given mutation. These types of studies are the first glimpse presaging an exciting new period in craniofacial research – one in which the identification of candidate human mutations resulting from genome-wide sequence analysis can be allied with the new gene-editing approaches and available mutant resources in animal models for the rapid expansion of our understanding and ap- pre Q10 ciation of this fascinating developmental system.Araki et al. (2004), Ashe et al. (2012), Bajpai et al. (2010), Barbaric et al. (2008), Bonnard et al. (2012), Bourgeois et al. (1998), Bush et al. (2004), Feng et al. (2008), Ghoumid et al. (2013), Hernandez-Porras et al. (2014), Hu et al. (2015,Hu et al. (2014), Momb et al. (2013), Nissen et al. (2006), Ueda et al., (2006), Wang et al. (2005Yanagisawa et al. (2003) andYin et al. (2008). "
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    ABSTRACT: The craniofacial skeletal structures that comprise the human head develop from multiple tissues that converge to form the bones and cartilage of the face. Because of their complex development and morphogenesis, many human birth defects arise due to disruptions in these cellular populations. Thus, determining how these structures normally develop is vital if we are to gain a deeper understanding of craniofacial birth defects and devise treatment and prevention options. In this review, we will focus on how animal model systems have been used historically and in an ongoing context to enhance our understanding of human craniofacial development. We do this by first highlighting “animal to man” approaches: that is, how animal models are being utilized to understand fundamental mechanisms of craniofacial development. We discuss emerging technologies, including high throughput sequencing and genome editing, and new animal repository resources, and how their application can revolutionize the future of animal models in craniofacial research. Secondly, we highlight “man to animal” approaches, including the current use of animal models to test the function of candidate human disease variants. Specifically, we outline a common workflow deployed after discovery of a potentially disease causing variant based on a select set of recent examples in which human mutations are investigated in vivo using animal models. Collectively, these topics will provide a pipeline for the use of animal models in understanding human craniofacial development and disease for clinical geneticist and basic researchers alike.
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    • "Given the similarities in hominid gestational environment, we hypothesized that non-human primate CNCCs could be derived from pluripotent cells using the same cell culture conditions that we have previously applied to human embryonic stem cells (ESCs)/iPSCs (Bajpai et al., 2010; Rada-Iglesias et al., 2012). Chimp iPSCs have recently become available and can be maintained in vitro under identical conditions as human ESCs/iPSCs (Marchetto et al., 2013). "
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    • "There are three known developmental origins for the cells that make up the mature heart: the cardiogenic mesoderm, from which the myocardium and endocardium are derived (Saga et al., 1999); cardiac NCCs, which contribute to OFT septation and great vessel development (Creazzo et al., 1998; Waldo et al., 2005); and the proepicardial organ, which provides components of the coronary vasculature system (Merki et al., 2005). CHARGE syndrome is often classified as a disease arising from maldevelopment of NCCs, known as a neurocristopathy (Etchevers et al., 2006), and CHD7 activity has been shown to have an essential role in the activation of the NCC transcriptional circuitry (Bajpai et al., 2010). We show for the first time that loss of Chd7 in the early cardiogenic mesoderm , driven by Mesp1-Cre, results in major structural defects and gene dysregulation, leading to cardiac failure and embryonic lethality around E15.5. "
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