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


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
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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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    ABSTRACT: cis-regulatory changes play a central role in mor- phological divergence, yet the regulatory principles underlying emergence of human traits remain poorly understood. Here, we use epigenomic profiling from human and chimpanzee cranial neural crest cells to systematically and quantitatively annotate diver- gence of craniofacial cis-regulatory landscapes. Epi- genomic divergence is often attributable to genetic variation within TF motifs at orthologous enhancers, with a novel motif being most predictive of activity biases. We explore properties of this cis-regulatory change, revealing the role of particular retroele- ments, uncovering broad clusters of species-biased enhancers near genes associated with human facial variation, and demonstrating that cis-regulatory divergence is linked to quantitative expression differ- ences of crucial neural crest regulators. Our work provides a wealth of candidates for future evolu- tionary studies and demonstrates the value of ‘‘cellular anthropology,’’ a strategy of using in-vitro- derived embryonic cell types to elucidate both fundamental and evolving mechanisms underlying morphological variation in higher primates
    Cell 09/2015; 163. DOI:10.1016/j.cell.2015.08.036 · 32.24 Impact Factor
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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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    ABSTRACT: CHARGE syndrome is caused by spontaneous loss-of-function mutations to the ATP-dependent chromatin remodeller chromodomain-helicase-DNA-binding protein 7 (CHD7). It is characterised by a distinct pattern of congenital anomalies, including cardiovascular malformations. Disruption to the neural crest lineage has previously been emphasised in the etiology of this developmental disorder. We present evidence for an additional requirement for CHD7 activity in the Mesp1-expressing anterior mesoderm during heart development. Conditional ablation of Chd7 in this lineage results in major structural cardiovascular defects akin to those seen in CHARGE patients, as well as a striking loss of cardiac innervation and embryonic lethality. Genome-wide transcriptional analysis identified aberrant expression of key components of the Class 3 Semaphorin and Slit-Robo signalling pathways in Chd7(fl/fl);Mesp1-Cre mutant hearts. CHD7 localises at the Sema3c promoter in vivo, with alteration of the local chromatin structure seen following Chd7 ablation, suggestive of direct transcriptional regulation. Furthermore, we uncover a novel role for CHD7 activity upstream of critical calcium handling genes, and demonstrate an associated functional defect in the ability of cardiomyocytes to undergo excitation-contraction coupling. This work therefore reveals the importance of CHD7 in the cardiogenic mesoderm for multiple processes during cardiovascular development. Copyright © 2015. Published by Elsevier Inc.
    Developmental Biology 06/2015; 89(1). DOI:10.1016/j.ydbio.2015.06.017 · 3.55 Impact Factor
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    • "It encodes for the chromodomain helicase DNA binding protein, a member of the chromodomain family. In human neural crest cells, CHD7 forms a protein complex with PBAF (polybromo-and BRG1-associated factor-containing complex) that regulates chromatin structure, gene expression and embryonic development (Bajpai et al., 2010; Hargreaves and Crabtree, 2011). Currently, CHD7 is the only gene known to be associated with the CHARGE syndrome (Lalani et al., 2006); both heterozygous mutations and deletions of CHD7 could result in CHARGE syndrome. "
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    ABSTRACT: In Genetics Out-patient Department of Shanghai Children's Medical Center, we consulted a 3-year-old boy with multiple anomaly syndrome (congenital heart disease, cryptorchidism, congenital deafness, mental retardation, exophthalmos, laryngeal cartilage dysplasia and high arched palate). We ruled out the possibility of multiple deformities caused by genomic imbalances. The patient was then clinically considered to have CHARGE syndrome, an autosomal dominant multi-system disorder involving defects in multiple organs, and CHD7 is the only known gene associated with the syndrome. Sequencing analysis of CHD7 of the proband identified a de novo heterogeneous mutation (c.2916_2917del, p.Gln972HisfsX22), a two-nucleotide deletion causing reading frame shift and resulting in a truncated CHD7 protein. Computational structure analysis suggests that the truncated protein only contains the chromodomains of CHD7, but lacks the SWI2/SNF2-like ATPase/helicase domain and the DNA binding domain, which are indispensable for the proper function of the protein, especially on chromatin remodeling. The patient then received follow up treatment in different clinical departments in a long period. To our best knowledge, this is the first CHARGE syndrome in Chinese patients diagnosed by gene analysis. In summary, the clinical symptoms and the description of treatment in the present case, combined with genetic test and functional prediction of CHD7, are helpful for further understanding and genetic counseling of the CHARGE syndrome.
    Meta Gene 12/2014; 2:469–478. DOI:10.1016/j.mgene.2014.06.002
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