title: Identification of novel craniofacial regulatory domains located far upstream of SOX9 and disrupted in Pierre Robin sequence.
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.
authors.affiliation: Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Gordon
authors.forename: Catia
authors.initials: C
authors.lastname: Attanasio
authors.forename: Shipra
authors.initials: S
authors.lastname: Bhatia
authors.forename: Sabina
authors.initials: S
authors.lastname: Benko
authors.forename: Morad
authors.initials: M
authors.lastname: Ansari
authors.forename: Tiong Y
authors.initials: TY
authors.lastname: Tan
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.forename: Véronique
authors.initials: V
authors.lastname: Abadie
authors.forename: I Karen
authors.initials: IK
authors.lastname: Temple
authors.forename: Alice
authors.initials: A
authors.lastname: Goldenberg
authors.forename: Veronica
authors.initials: V
authors.lastname: van Heyningen
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: David
authors.initials: D
authors.lastname: FitzPatrick
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Kleinjan
authors.forename: Axel
authors.initials: A
authors.lastname: Visel
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D055036:Campomelic Dysplasia / Q000235:genetics* / Q000473:pathology; D002648:Child; D002886:Chromosomes, Human, Pair 17; D004742:Enhancer Elements, Genetic; D005260:Female; D056426:Genetic Loci; D006801:Humans; D008297:Male; D008334:Mandible / Q000002:abnormalities / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010855:Pierre Robin Syndrome / Q000235:genetics* / Q000473:pathology; D055758:SOX9 Transcription Factor / Q000235:genetics*; D015027:Zebrafish; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D055758:SOX9 Transcription Factor; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse
keywords: Pierre Robin; SOX9; campomelic dysplasia; craniofacial; enhancer; long-range regulation