Identification of Novel Craniofacial Regulatory Domains Located far Upstream of SOX9 and Disrupted in Pierre Robin Sequence |
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| Authors: | Christopher T. Gordon Catia Attanasio Shipra Bhatia Sabina Benko Morad Ansari Tiong Y. Tan Arnold Munnich Len A. Pennacchio Véronique Abadie I. Karen Temple Alice Goldenberg Veronica van Heyningen Jeanne Amiel David FitzPatrick Dirk A. Kleinjan Axel Visel Stanislas Lyonnet |
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| Affiliation: | 1. Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France;2. Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California;3. Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland;4. MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK;5. Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York City, New York;6. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia;7. H?pital Necker‐Enfants Malades AP‐HP, Paris, France;8. U.S. Department of Energy Joint Genome Institute, Walnut Creek, California;9. Service de Pédiatrie Générale, Université Paris Descartes, H?pital Necker‐Enfants Malades, Paris, France;10. Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK;11. Service de Génétique Médicale, CHU Charles Nicolle, Rouen, France;12. School of Natural Sciences, University of California, Merced, California |
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| Abstract: | Mutations in the coding sequence of SOX9 cause campomelic dysplasia (CD), a disorder of skeletal development associated with 46,XY disorders of sex development (DSDs). Translocations, deletions, and duplications within a ～2 Mb region upstream of SOX9 can recapitulate the CD–DSD phenotype fully or partially, suggesting the existence of an unusually large cis‐regulatory control region. Pierre Robin sequence (PRS) is a craniofacial disorder that is frequently an endophenotype of CD and a locus for isolated PRS at ～1.2–1.5 Mb upstream of SOX9 has been previously reported. The craniofacial regulatory potential within this locus, and within the greater genomic domain surrounding SOX9, remains poorly defined. We report two novel deletions upstream of SOX9 in families with PRS, allowing refinement of the regions harboring candidate craniofacial regulatory elements. In parallel, ChIP‐Seq for p300 binding sites in mouse craniofacial tissue led to the identification of several novel craniofacial enhancers at the SOX9 locus, which were validated in transgenic reporter mice and zebrafish. Notably, some of the functionally validated elements fall within the PRS deletions. These studies suggest that multiple noncoding elements contribute to the craniofacial regulation of SOX9 expression, and that their disruption results in PRS. |
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| Keywords: | SOX9 craniofacial enhancer Pierre Robin long‐range regulation campomelic dysplasia |
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