The University of Southampton
University of Southampton Institutional Repository

Identification of novel craniofacial regulatory domains located far upstream of SOX9 and disrupted in Pierre Robin sequence

Identification of novel craniofacial regulatory domains located far upstream of SOX9 and disrupted in Pierre Robin sequence
Identification of novel craniofacial regulatory domains located far upstream of SOX9 and disrupted in Pierre Robin sequence
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.
SOX9, craniofacial, enhancer, pierre robin, long-range regulation, campomelic dysplasia
1059-7794
1011-1020
Gordon, Christopher T.
02c1211b-e91c-4a21-8bfd-2c30d1e1d0cf
Attanasio, Catia
54b62377-2fab-4a90-a278-82abdff32ad5
Bhatia, Shipra
285778a6-a569-47a3-812d-4e5dd95fcc7e
Benko, Sabina
25e8b27d-67de-4c6f-a27b-ee9cca0b18e2
Ansari, Morad
b4831f76-cd33-4ba7-91bb-393d8acdc137
Tan, Tiong Y.
c8e7c32f-879f-4094-8cb2-d547e260ec1e
Munnich, Arnold
31088998-7bf3-4a2b-9f4b-513f2012ed46
Pennacchio, Len A.
134ba961-59e6-460f-a447-116b5f4a2059
Abadie, Véronique
51e9a39b-da7b-4505-b534-d6cef74f8d89
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Goldenberg, Alice
ff95bdfb-469a-4f40-9e8f-bb586e9863a5
van Heyningen, Veronica
08323cb8-896e-4a4b-a8cf-9066ec37254e
Amiel, Jeanne
b94c482b-1c03-43c0-8940-7aa9ed948141
FitzPatrick, David
165802b4-67a8-422b-8619-737354cca8ab
Kleinjan, Dirk A.
4df08aad-bad4-4963-8d6d-61072b5a0e98
Visel, Axel
bf685d11-69e4-4e83-bca5-a53daf468e10
Lyonnet, Stanislas
7706ebd0-c789-4df1-8c34-eaac18e457c3
Gordon, Christopher T.
02c1211b-e91c-4a21-8bfd-2c30d1e1d0cf
Attanasio, Catia
54b62377-2fab-4a90-a278-82abdff32ad5
Bhatia, Shipra
285778a6-a569-47a3-812d-4e5dd95fcc7e
Benko, Sabina
25e8b27d-67de-4c6f-a27b-ee9cca0b18e2
Ansari, Morad
b4831f76-cd33-4ba7-91bb-393d8acdc137
Tan, Tiong Y.
c8e7c32f-879f-4094-8cb2-d547e260ec1e
Munnich, Arnold
31088998-7bf3-4a2b-9f4b-513f2012ed46
Pennacchio, Len A.
134ba961-59e6-460f-a447-116b5f4a2059
Abadie, Véronique
51e9a39b-da7b-4505-b534-d6cef74f8d89
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Goldenberg, Alice
ff95bdfb-469a-4f40-9e8f-bb586e9863a5
van Heyningen, Veronica
08323cb8-896e-4a4b-a8cf-9066ec37254e
Amiel, Jeanne
b94c482b-1c03-43c0-8940-7aa9ed948141
FitzPatrick, David
165802b4-67a8-422b-8619-737354cca8ab
Kleinjan, Dirk A.
4df08aad-bad4-4963-8d6d-61072b5a0e98
Visel, Axel
bf685d11-69e4-4e83-bca5-a53daf468e10
Lyonnet, Stanislas
7706ebd0-c789-4df1-8c34-eaac18e457c3

Gordon, Christopher T., Attanasio, Catia, Bhatia, Shipra, Benko, Sabina, Ansari, Morad, Tan, Tiong Y., Munnich, Arnold, Pennacchio, Len A., Abadie, Véronique, Temple, I. Karen, Goldenberg, Alice, van Heyningen, Veronica, Amiel, Jeanne, FitzPatrick, David, Kleinjan, Dirk A., Visel, Axel and Lyonnet, Stanislas (2014) Identification of novel craniofacial regulatory domains located far upstream of SOX9 and disrupted in Pierre Robin sequence. Human Mutation, 35 (8), 1011-1020. (doi:10.1002/humu.22606). (PMID:24934569)

Record type: Article

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.

Text
Text - Accepted Manuscript
Download (324kB)
Slideshow
Figures - Accepted Manuscript
Download (3MB)

More information

Accepted/In Press date: 12 May 2014
e-pub ahead of print date: 17 July 2014
Published date: August 2014
Keywords: SOX9, craniofacial, enhancer, pierre robin, long-range regulation, campomelic dysplasia
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 366026
URI: http://eprints.soton.ac.uk/id/eprint/366026
ISSN: 1059-7794
PURE UUID: 0cbe90a5-2def-4647-996f-c667b8c7e3b2
ORCID for I. Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781

Catalogue record

Date deposited: 20 Jun 2014 12:37
Last modified: 15 Mar 2024 03:00

Export record

Altmetrics

Contributors

Author: Christopher T. Gordon
Author: Catia Attanasio
Author: Shipra Bhatia
Author: Sabina Benko
Author: Morad Ansari
Author: Tiong Y. Tan
Author: Arnold Munnich
Author: Len A. Pennacchio
Author: Véronique Abadie
Author: I. Karen Temple ORCID iD
Author: Alice Goldenberg
Author: Veronica van Heyningen
Author: Jeanne Amiel
Author: David FitzPatrick
Author: Dirk A. Kleinjan
Author: Axel Visel
Author: Stanislas Lyonnet

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×