This sequence of anomalies, in turn, results in feeding and breathing difficulties and failure to thrive ( Rathé et al., 2015). In some cases, the perturbed enhancers have been mapped and characterized for example, an SRY-responsive regulatory element essential for sex determination ( Gonen et al., 2018).Ī cluster of large genomic deletions and translocation breakpoints at the centromeric far end of the SOX9 TAD are associated with isolated Pierre Robin sequence (PRS), a congenital craniofacial disorder characterized by a single primary phenotype: underdevelopment of the lower jaw or mandible (micrognathia) that leads to secondary phenotypes, including retraction of the tongue (glossoptosis), obstruction of the airway, and, with incomplete penetrance, horseshoe-shaped cleft palate ( Robin, 1994 Tan and Farlie, 2013). Many non-coding mutations have been described within this gene desert, including large deletions, translocations, and duplications, that cause a range of defects that recapitulate distinct aspects, but not all features, of campomelic dysplasia, leading to the hypothesis that cell-type-specific enhancers are disrupted in these tissue-selective disorders ( Baetens et al., 2017 Kurth et al., 2009 Sanchez-Castro et al., 2013). Interestingly, SOX9 is the sole protein-coding gene within an unusually large, ~2-Mb topologically associating domain (TAD) ( Bagheri-Fam et al., 2006 Gordon et al., 2009). Heterozygous loss-of-function mutations in the SOX9 coding sequence cause a severe congenital disorder called campomelic dysplasia, which is associated with bowed long limbs, disorders of sex determination, and craniofacial defects ( Wagner et al., 1994). For example, SOX9, an SRY (sex-determining region Y)-related HMG (high mobility group) box (SOX) transcription factor, plays numerous important roles during embryogenesis, including sex determination, chondrogenesis, and craniofacial development ( Lee and Saint-Jeannet, 2011 Lefebvre and Dvir-Ginzberg, 2016). Although mutations of protein-coding sequences often affect multiple tissues in which a given gene is active, mutations in non-coding regulatory regions can selectively perturb target gene expression in specific tissue contexts.
Non-coding mutations are increasingly being implicated in human disease ( Franke et al., 2016 Laugsch et al., 2019 Lupiáñez et al., 2015), and, in particular, perturbations of enhancers have been documented as being causative because of their effects on gene regulation during development ( Spitz, 2016). Overall, we characterize the longest-range human enhancers involved in congenital malformations, directly demonstrate that PRS is an enhanceropathy, and illustrate how small changes in gene expression can lead to morphological variation.ĭistal regulatory sequences called enhancers control gene transcription at a distance and play a critical role in directing developmental gene expression patterns ( Long et al., 2016). Using mouse models, we demonstrate that PRS phenotypic specificity arises from the convergence of two mechanisms: confinement of Sox9 dosage perturbation to developing facial structures through context-specific enhancer activity and heightened sensitivity of the lower jaw to Sox9 expression reduction.
Enhancers within the 1.45 Mb cluster exhibit highly synergistic activity that is dependent on the Coordinator motif. Leveraging a human stem cell differentiation model, we identify two clusters of enhancers within the PRS-associated region that regulate SOX9 expression during a restricted window of facial progenitor development at distances up to 1.45 Mb. Non-coding mutations at the far end of a large gene desert surrounding the SOX9 gene result in a human craniofacial disorder called Pierre Robin sequence (PRS).
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