Identification of Novel Craniofacial Regulatory Domains Located far Upstream of SOX9 and Disrupted in Pierre Robin Sequence
Identifieur interne : 000E21 ( Istex/Corpus ); précédent : 000E20; suivant : 000E22Identification of Novel Craniofacial Regulatory Domains Located far Upstream of SOX9 and Disrupted in Pierre Robin Sequence
Auteurs : 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 LyonnetSource :
- Human Mutation [ 1059-7794 ] ; 2014-08.
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.
Url:
DOI: 10.1002/humu.22606
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Identification of Novel Craniofacial Regulatory Domains Located far Upstream of SOX9 and Disrupted in Pierre Robin Sequence</title><author><name sortKey="Gordon, Christopher T" sort="Gordon, Christopher T" uniqKey="Gordon C" first="Christopher T." last="Gordon">Christopher T. Gordon</name><affiliation><mods:affiliation>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: chris.gordon@inserm.fr</mods:affiliation></affiliation></author><author><name sortKey="Attanasio, Catia" sort="Attanasio, Catia" uniqKey="Attanasio C" first="Catia" last="Attanasio">Catia Attanasio</name><affiliation><mods:affiliation>Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California</mods:affiliation></affiliation><affiliation><mods:affiliation>Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Bhatia, Shipra" sort="Bhatia, Shipra" uniqKey="Bhatia S" first="Shipra" last="Bhatia">Shipra Bhatia</name><affiliation><mods:affiliation>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</mods:affiliation></affiliation></author><author><name sortKey="Benko, Sabina" sort="Benko, Sabina" uniqKey="Benko S" first="Sabina" last="Benko">Sabina Benko</name><affiliation><mods:affiliation>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York City</mods:affiliation></affiliation></author><author><name sortKey="Ansari, Morad" sort="Ansari, Morad" uniqKey="Ansari M" first="Morad" last="Ansari">Morad Ansari</name><affiliation><mods:affiliation>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</mods:affiliation></affiliation></author><author><name sortKey="Tan, Tiong Y" sort="Tan, Tiong Y" uniqKey="Tan T" first="Tiong Y." last="Tan">Tiong Y. Tan</name><affiliation><mods:affiliation>Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia</mods:affiliation></affiliation></author><author><name sortKey="Munnich, Arnold" sort="Munnich, Arnold" uniqKey="Munnich A" first="Arnold" last="Munnich">Arnold Munnich</name><affiliation><mods:affiliation>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Hôpital Necker‐Enfants Malades AP‐HP, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Pennacchio, Len A" sort="Pennacchio, Len A" uniqKey="Pennacchio L" first="Len A." last="Pennacchio">Len A. Pennacchio</name><affiliation><mods:affiliation>Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California</mods:affiliation></affiliation><affiliation><mods:affiliation>U.S. Department of Energy Joint Genome Institute, California, Walnut Creek</mods:affiliation></affiliation></author><author><name sortKey="Abadie, Veronique" sort="Abadie, Veronique" uniqKey="Abadie V" first="Véronique" last="Abadie">Véronique Abadie</name><affiliation><mods:affiliation>Service de Pédiatrie Générale, Université Paris Descartes, Hôpital Necker‐Enfants Malades, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Temple, I Karen" sort="Temple, I Karen" uniqKey="Temple I" first="I. Karen" last="Temple">I. Karen Temple</name><affiliation><mods:affiliation>Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK</mods:affiliation></affiliation></author><author><name sortKey="Goldenberg, Alice" sort="Goldenberg, Alice" uniqKey="Goldenberg A" first="Alice" last="Goldenberg">Alice Goldenberg</name><affiliation><mods:affiliation>Service de Génétique Médicale, CHU Charles Nicolle, Rouen, France</mods:affiliation></affiliation></author><author><name sortKey="Van Heyningen, Veronica" sort="Van Heyningen, Veronica" uniqKey="Van Heyningen V" first="Veronica" last="Van Heyningen">Veronica Van Heyningen</name><affiliation><mods:affiliation>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</mods:affiliation></affiliation></author><author><name sortKey="Amiel, Jeanne" sort="Amiel, Jeanne" uniqKey="Amiel J" first="Jeanne" last="Amiel">Jeanne Amiel</name><affiliation><mods:affiliation>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Hôpital Necker‐Enfants Malades AP‐HP, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Fitzpatrick, David" sort="Fitzpatrick, David" uniqKey="Fitzpatrick D" first="David" last="Fitzpatrick">David Fitzpatrick</name><affiliation><mods:affiliation>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</mods:affiliation></affiliation></author><author><name sortKey="Kleinjan, Dirk A" sort="Kleinjan, Dirk A" uniqKey="Kleinjan D" first="Dirk A." last="Kleinjan">Dirk A. Kleinjan</name><affiliation><mods:affiliation>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</mods:affiliation></affiliation></author><author><name sortKey="Visel, Axel" sort="Visel, Axel" uniqKey="Visel A" first="Axel" last="Visel">Axel Visel</name><affiliation><mods:affiliation>Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California</mods:affiliation></affiliation><affiliation><mods:affiliation>U.S. Department of Energy Joint Genome Institute, Walnut Creek, California</mods:affiliation></affiliation><affiliation><mods:affiliation>School of Natural Sciences, University of California, California, Merced</mods:affiliation></affiliation></author><author><name sortKey="Lyonnet, Stanislas" sort="Lyonnet, Stanislas" uniqKey="Lyonnet S" first="Stanislas" last="Lyonnet">Stanislas Lyonnet</name><affiliation><mods:affiliation>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Hôpital Necker‐Enfants Malades AP‐HP, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: chris.gordon@inserm.fr</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:4B65229FDA86C14B5421D0AC7CAEB415D7BAB56F</idno><date when="2014" year="2014">2014</date><idno type="doi">10.1002/humu.22606</idno><idno type="url">https://api.istex.fr/document/4B65229FDA86C14B5421D0AC7CAEB415D7BAB56F/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000E21</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000E21</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main">Identification of Novel Craniofacial Regulatory Domains Located far Upstream of <hi rend="italic"><hi rend="fc">SOX</hi>9</hi> and Disrupted in Pierre Robin Sequence</title><author><name sortKey="Gordon, Christopher T" sort="Gordon, Christopher T" uniqKey="Gordon C" first="Christopher T." last="Gordon">Christopher T. Gordon</name><affiliation><mods:affiliation>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: chris.gordon@inserm.fr</mods:affiliation></affiliation></author><author><name sortKey="Attanasio, Catia" sort="Attanasio, Catia" uniqKey="Attanasio C" first="Catia" last="Attanasio">Catia Attanasio</name><affiliation><mods:affiliation>Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California</mods:affiliation></affiliation><affiliation><mods:affiliation>Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Bhatia, Shipra" sort="Bhatia, Shipra" uniqKey="Bhatia S" first="Shipra" last="Bhatia">Shipra Bhatia</name><affiliation><mods:affiliation>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</mods:affiliation></affiliation></author><author><name sortKey="Benko, Sabina" sort="Benko, Sabina" uniqKey="Benko S" first="Sabina" last="Benko">Sabina Benko</name><affiliation><mods:affiliation>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York City</mods:affiliation></affiliation></author><author><name sortKey="Ansari, Morad" sort="Ansari, Morad" uniqKey="Ansari M" first="Morad" last="Ansari">Morad Ansari</name><affiliation><mods:affiliation>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</mods:affiliation></affiliation></author><author><name sortKey="Tan, Tiong Y" sort="Tan, Tiong Y" uniqKey="Tan T" first="Tiong Y." last="Tan">Tiong Y. Tan</name><affiliation><mods:affiliation>Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia</mods:affiliation></affiliation></author><author><name sortKey="Munnich, Arnold" sort="Munnich, Arnold" uniqKey="Munnich A" first="Arnold" last="Munnich">Arnold Munnich</name><affiliation><mods:affiliation>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Hôpital Necker‐Enfants Malades AP‐HP, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Pennacchio, Len A" sort="Pennacchio, Len A" uniqKey="Pennacchio L" first="Len A." last="Pennacchio">Len A. Pennacchio</name><affiliation><mods:affiliation>Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California</mods:affiliation></affiliation><affiliation><mods:affiliation>U.S. Department of Energy Joint Genome Institute, California, Walnut Creek</mods:affiliation></affiliation></author><author><name sortKey="Abadie, Veronique" sort="Abadie, Veronique" uniqKey="Abadie V" first="Véronique" last="Abadie">Véronique Abadie</name><affiliation><mods:affiliation>Service de Pédiatrie Générale, Université Paris Descartes, Hôpital Necker‐Enfants Malades, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Temple, I Karen" sort="Temple, I Karen" uniqKey="Temple I" first="I. Karen" last="Temple">I. Karen Temple</name><affiliation><mods:affiliation>Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK</mods:affiliation></affiliation></author><author><name sortKey="Goldenberg, Alice" sort="Goldenberg, Alice" uniqKey="Goldenberg A" first="Alice" last="Goldenberg">Alice Goldenberg</name><affiliation><mods:affiliation>Service de Génétique Médicale, CHU Charles Nicolle, Rouen, France</mods:affiliation></affiliation></author><author><name sortKey="Van Heyningen, Veronica" sort="Van Heyningen, Veronica" uniqKey="Van Heyningen V" first="Veronica" last="Van Heyningen">Veronica Van Heyningen</name><affiliation><mods:affiliation>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</mods:affiliation></affiliation></author><author><name sortKey="Amiel, Jeanne" sort="Amiel, Jeanne" uniqKey="Amiel J" first="Jeanne" last="Amiel">Jeanne Amiel</name><affiliation><mods:affiliation>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Hôpital Necker‐Enfants Malades AP‐HP, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Fitzpatrick, David" sort="Fitzpatrick, David" uniqKey="Fitzpatrick D" first="David" last="Fitzpatrick">David Fitzpatrick</name><affiliation><mods:affiliation>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</mods:affiliation></affiliation></author><author><name sortKey="Kleinjan, Dirk A" sort="Kleinjan, Dirk A" uniqKey="Kleinjan D" first="Dirk A." last="Kleinjan">Dirk A. Kleinjan</name><affiliation><mods:affiliation>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</mods:affiliation></affiliation></author><author><name sortKey="Visel, Axel" sort="Visel, Axel" uniqKey="Visel A" first="Axel" last="Visel">Axel Visel</name><affiliation><mods:affiliation>Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California</mods:affiliation></affiliation><affiliation><mods:affiliation>U.S. Department of Energy Joint Genome Institute, Walnut Creek, California</mods:affiliation></affiliation><affiliation><mods:affiliation>School of Natural Sciences, University of California, California, Merced</mods:affiliation></affiliation></author><author><name sortKey="Lyonnet, Stanislas" sort="Lyonnet, Stanislas" uniqKey="Lyonnet S" first="Stanislas" last="Lyonnet">Stanislas Lyonnet</name><affiliation><mods:affiliation>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Hôpital Necker‐Enfants Malades AP‐HP, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: chris.gordon@inserm.fr</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Human Mutation</title><title level="j" type="alt">HUMAN MUTATION</title><idno type="ISSN">1059-7794</idno><idno type="eISSN">1098-1004</idno><imprint><biblScope unit="vol">35</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="1011">1011</biblScope><biblScope unit="page" to="1020">1020</biblScope><biblScope unit="page-count">10</biblScope><date type="published" when="2014-08">2014-08</date></imprint><idno type="ISSN">1059-7794</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1059-7794</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="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.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Christopher T. Gordon</name><affiliations><json:string>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</json:string><json:string>E-mail: chris.gordon@inserm.fr</json:string></affiliations></json:item><json:item><name>Catia Attanasio</name><affiliations><json:string>Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California</json:string><json:string>Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland</json:string></affiliations></json:item><json:item><name>Shipra Bhatia</name><affiliations><json:string>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</json:string></affiliations></json:item><json:item><name>Sabina Benko</name><affiliations><json:string>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</json:string><json:string>Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York City</json:string></affiliations></json:item><json:item><name>Morad Ansari</name><affiliations><json:string>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</json:string></affiliations></json:item><json:item><name>Tiong Y. Tan</name><affiliations><json:string>Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia</json:string></affiliations></json:item><json:item><name>Arnold Munnich</name><affiliations><json:string>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</json:string><json:string>Hôpital Necker‐Enfants Malades AP‐HP, Paris, France</json:string></affiliations></json:item><json:item><name>Len A. Pennacchio</name><affiliations><json:string>Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California</json:string><json:string>U.S. Department of Energy Joint Genome Institute, California, Walnut Creek</json:string></affiliations></json:item><json:item><name>Véronique Abadie</name><affiliations><json:string>Service de Pédiatrie Générale, Université Paris Descartes, Hôpital Necker‐Enfants Malades, Paris, France</json:string></affiliations></json:item><json:item><name>I. Karen Temple</name><affiliations><json:string>Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK</json:string></affiliations></json:item><json:item><name>Alice Goldenberg</name><affiliations><json:string>Service de Génétique Médicale, CHU Charles Nicolle, Rouen, France</json:string></affiliations></json:item><json:item><name>Veronica van Heyningen</name><affiliations><json:string>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</json:string></affiliations></json:item><json:item><name>Jeanne Amiel</name><affiliations><json:string>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</json:string><json:string>Hôpital Necker‐Enfants Malades AP‐HP, Paris, France</json:string></affiliations></json:item><json:item><name>David FitzPatrick</name><affiliations><json:string>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</json:string></affiliations></json:item><json:item><name>Dirk A. Kleinjan</name><affiliations><json:string>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</json:string></affiliations></json:item><json:item><name>Axel Visel</name><affiliations><json:string>Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California</json:string><json:string>U.S. Department of Energy Joint Genome Institute, Walnut Creek, California</json:string><json:string>School of Natural Sciences, University of California, California, Merced</json:string></affiliations></json:item><json:item><name>Stanislas Lyonnet</name><affiliations><json:string>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</json:string><json:string>Hôpital Necker‐Enfants Malades AP‐HP, Paris, France</json:string><json:string>E-mail: chris.gordon@inserm.fr</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>SOX9</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>craniofacial</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>enhancer</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Pierre Robin</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>long‐range regulation</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>campomelic dysplasia</value></json:item></subject><articleId><json:string>HUMU22606</json:string></articleId><arkIstex>ark:/67375/WNG-25S05PLL-5</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>The craniofacial regulatory potential of non‐coding DNA upstream of SOX9 has not been fully mapped. ChIP‐Seq analysis led to the identification of candidate SOX9 craniofacial enhancers. In transgenic zebrafish embryos, one of these elements, peak 17, drove expression of a GFP reporter gene in the pharyngeal arches. This element falls with deletions observed in Pierre Robin sequence (PRS) patients; loss of the element in these patients may result in abnormal expression of SOX9, leading to the craniofacial phenotype of PRS.</abstract><qualityIndicators><score>9.28</score><pdfWordCount>6891</pdfWordCount><pdfCharCount>43529</pdfCharCount><pdfVersion>1.4</pdfVersion><pdfPageCount>10</pdfPageCount><pdfPageSize>595.245 x 793.92 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractWordCount>190</abstractWordCount><abstractCharCount>1335</abstractCharCount><keywordCount>6</keywordCount></qualityIndicators><title>Identification of Novel Craniofacial Regulatory Domains Located far Upstream of SOX9 and Disrupted in Pierre Robin Sequence</title><genre><json:string>article</json:string></genre><host><title>Human Mutation</title><language><json:string>unknown</json:string></language><doi><json:string>10.1002/(ISSN)1098-1004</json:string></doi><issn><json:string>1059-7794</json:string></issn><eissn><json:string>1098-1004</json:string></eissn><publisherId><json:string>HUMU</json:string></publisherId><volume>35</volume><issue>8</issue><pages><first>1011</first><last>1020</last><total>10</total></pages><genre><json:string>journal</json:string></genre><subject><json:item><value>Research Article</value></json:item></subject></host><ark><json:string>ark:/67375/WNG-25S05PLL-5</json:string></ark><publicationDate>2014</publicationDate><copyrightDate>2014</copyrightDate><doi><json:string>10.1002/humu.22606</json:string></doi><id>4B65229FDA86C14B5421D0AC7CAEB415D7BAB56F</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/4B65229FDA86C14B5421D0AC7CAEB415D7BAB56F/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/4B65229FDA86C14B5421D0AC7CAEB415D7BAB56F/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/4B65229FDA86C14B5421D0AC7CAEB415D7BAB56F/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main">Identification of Novel Craniofacial Regulatory Domains Located far Upstream of <hi rend="italic"><hi rend="fc">SOX</hi>9</hi> and Disrupted in Pierre Robin Sequence</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Publishing Ltd</publisher><availability><licence>© 2014 WILEY PERIODICALS, INC.</licence></availability><date type="published" when="2014-08"></date></publicationStmt><notesStmt><note type="content-type" subtype="article" source="article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</note><note type="publication-type" subtype="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="article"><analytic><title level="a" type="main">Identification of Novel Craniofacial Regulatory Domains Located far Upstream of <hi rend="italic"><hi rend="fc">SOX</hi>9</hi> and Disrupted in Pierre Robin Sequence</title><author xml:id="author-0000" role="corresp"><persName><forename type="first">Christopher T.</forename><surname>Gordon</surname></persName><affiliation><orgName>Université Paris Descartes–Sorbonne Paris Cité</orgName><orgName>Institut Imagine, INSERM U1163</orgName><address><settlement type="city">Paris</settlement><country key="FR">France</country></address></affiliation><affiliation>Correspondence to: Chris Gordon or Stanislas Lyonnet, INSERM U1163, Institut Imagine, 24 Boulevard du Montparnasse, 75015, Paris France. E‐mail: chris.gordon@inserm.fr or stanislas.lyonnet@inserm.fr</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Catia</forename><surname>Attanasio</surname></persName><affiliation><orgName>Genomics Division</orgName><orgName>Lawrence Berkeley National Laboratory</orgName><address><settlement type="city">Berkeley</settlement><region>California</region></address></affiliation><affiliation><orgName>Center for Integrative Genomics, Faculty of Biology and Medicine</orgName><orgName>University of Lausanne</orgName><address><settlement type="city">Lausanne</settlement><country key="CH">Switzerland</country></address></affiliation></author><author xml:id="author-0002"><persName><forename type="first">Shipra</forename><surname>Bhatia</surname></persName><affiliation><orgName>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine</orgName><orgName>University of Edinburgh</orgName><address><settlement type="city">Edinburgh</settlement><country key="GB">UK</country></address></affiliation></author><author xml:id="author-0003"><persName><forename type="first">Sabina</forename><surname>Benko</surname></persName><affiliation><orgName>Université Paris Descartes–Sorbonne Paris Cité</orgName><orgName>Institut Imagine, INSERM U1163</orgName><address><settlement type="city">Paris</settlement><country key="FR">France</country></address></affiliation><affiliation><orgName>Department of Structural and Chemical Biology</orgName><orgName>Icahn School of Medicine at Mount Sinai</orgName><address><settlement type="city">New York City</settlement><region>New York</region></address></affiliation></author><author xml:id="author-0004"><persName><forename type="first">Morad</forename><surname>Ansari</surname></persName><affiliation><orgName>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine</orgName><orgName>University of Edinburgh</orgName><address><settlement type="city">Edinburgh</settlement><country key="GB">UK</country></address></affiliation></author><author xml:id="author-0005"><persName><forename type="first">Tiong Y.</forename><surname>Tan</surname></persName><affiliation><orgName>Victorian Clinical Genetics Services, Murdoch Children's Research Institute</orgName><orgName>Royal Children's Hospital</orgName><address><settlement type="city">Melbourne</settlement><country key="AU">Australia</country></address></affiliation></author><author xml:id="author-0006"><persName><forename type="first">Arnold</forename><surname>Munnich</surname></persName><affiliation><orgName>Université Paris Descartes–Sorbonne Paris Cité</orgName><orgName>Institut Imagine, INSERM U1163</orgName><address><settlement type="city">Paris</settlement><country key="FR">France</country></address></affiliation><affiliation><orgName>Hôpital Necker‐Enfants Malades AP‐HP</orgName><address><settlement type="city">Paris</settlement><country key="FR">France</country></address></affiliation></author><author xml:id="author-0007"><persName><forename type="first">Len A.</forename><surname>Pennacchio</surname></persName><affiliation><orgName>Genomics Division</orgName><orgName>Lawrence Berkeley National Laboratory</orgName><address><settlement type="city">Berkeley</settlement><region>California</region></address></affiliation><affiliation><orgName>U.S. Department of Energy Joint Genome Institute</orgName><address><settlement type="city">Walnut Creek</settlement><region>California</region></address></affiliation></author><author xml:id="author-0008"><persName><forename type="first">Véronique</forename><surname>Abadie</surname></persName><affiliation><orgName>Service de Pédiatrie Générale, Université Paris Descartes</orgName><orgName>Hôpital Necker‐Enfants Malades</orgName><address><settlement type="city">Paris</settlement><country key="FR">France</country></address></affiliation></author><author xml:id="author-0009"><persName><forename type="first">I. Karen</forename><surname>Temple</surname></persName><affiliation><orgName>Human Genetics and Genomic Medicine, Faculty of Medicine</orgName><orgName>University of Southampton</orgName><address><settlement type="city">Southampton</settlement><country key="GB">UK</country></address></affiliation></author><author xml:id="author-0010"><persName><forename type="first">Alice</forename><surname>Goldenberg</surname></persName><affiliation><orgName>Service de Génétique Médicale</orgName><orgName>CHU Charles Nicolle</orgName><address><settlement type="city">Rouen</settlement><country key="FR">France</country></address></affiliation></author><author xml:id="author-0011"><persName><forename type="first">Veronica</forename><surname>Heyningen</surname></persName><affiliation><orgName>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine</orgName><orgName>University of Edinburgh</orgName><address><settlement type="city">Edinburgh</settlement><country key="GB">UK</country></address></affiliation></author><author xml:id="author-0012"><persName><forename type="first">Jeanne</forename><surname>Amiel</surname></persName><affiliation><orgName>Université Paris Descartes–Sorbonne Paris Cité</orgName><orgName>Institut Imagine, INSERM U1163</orgName><address><settlement type="city">Paris</settlement><country key="FR">France</country></address></affiliation><affiliation><orgName>Hôpital Necker‐Enfants Malades AP‐HP</orgName><address><settlement type="city">Paris</settlement><country key="FR">France</country></address></affiliation></author><author xml:id="author-0013"><persName><forename type="first">David</forename><surname>FitzPatrick</surname></persName><affiliation><orgName>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine</orgName><orgName>University of Edinburgh</orgName><address><settlement type="city">Edinburgh</settlement><country key="GB">UK</country></address></affiliation></author><author xml:id="author-0014"><persName><forename type="first">Dirk A.</forename><surname>Kleinjan</surname></persName><affiliation><orgName>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine</orgName><orgName>University of Edinburgh</orgName><address><settlement type="city">Edinburgh</settlement><country key="GB">UK</country></address></affiliation></author><author xml:id="author-0015"><persName><forename type="first">Axel</forename><surname>Visel</surname></persName><affiliation><orgName>Genomics Division</orgName><orgName>Lawrence Berkeley National Laboratory</orgName><address><settlement type="city">Berkeley</settlement><region>California</region></address></affiliation><affiliation><orgName>U.S. Department of Energy Joint Genome Institute</orgName><address><settlement type="city">Walnut Creek</settlement><region>California</region></address></affiliation><affiliation><orgName>School of Natural Sciences</orgName><orgName>University of California</orgName><address><settlement type="city">Merced</settlement><region>California</region></address></affiliation></author><author xml:id="author-0016" role="corresp"><persName><forename type="first">Stanislas</forename><surname>Lyonnet</surname></persName><affiliation><orgName>Université Paris Descartes–Sorbonne Paris Cité</orgName><orgName>Institut Imagine, INSERM U1163</orgName><address><settlement type="city">Paris</settlement><country key="FR">France</country></address></affiliation><affiliation><orgName>Hôpital Necker‐Enfants Malades AP‐HP</orgName><address><settlement type="city">Paris</settlement><country key="FR">France</country></address></affiliation><affiliation>Correspondence to: Chris Gordon or Stanislas Lyonnet, INSERM U1163, Institut Imagine, 24 Boulevard du Montparnasse, 75015, Paris France. E‐mail: chris.gordon@inserm.fr or stanislas.lyonnet@inserm.fr</affiliation></author><idno type="istex">4B65229FDA86C14B5421D0AC7CAEB415D7BAB56F</idno><idno type="ark">ark:/67375/WNG-25S05PLL-5</idno><idno type="DOI">10.1002/humu.22606</idno><idno type="unit">HUMU22606</idno><idno type="toTypesetVersion">file:HUMU.HUMU22606.pdf</idno></analytic><monogr><title level="j" type="main">Human Mutation</title><title level="j" type="alt">HUMAN MUTATION</title><idno type="pISSN">1059-7794</idno><idno type="eISSN">1098-1004</idno><idno type="book-DOI">10.1002/(ISSN)1098-1004</idno><idno type="book-part-DOI">10.1002/humu.2014.35.issue-8</idno><idno type="product">HUMU</idno><imprint><biblScope unit="vol">35</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="1011">1011</biblScope><biblScope unit="page" to="1020">1020</biblScope><biblScope unit="page-count">10</biblScope><date type="published" when="2014-08"></date></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><abstract style="main"><head>ABSTRACT</head><p>Mutations in the coding sequence of <hi rend="italic"><hi rend="fc">SOX</hi>9</hi> cause campomelic dysplasia (<hi rend="fc">CD</hi>), a disorder of skeletal development associated with 46,<hi rend="fc">XY</hi> disorders of sex development (<hi rend="fc">DSD</hi>s). Translocations, deletions, and duplications within a ∼2 Mb region upstream of <hi rend="italic"><hi rend="fc">SOX</hi>9</hi> can recapitulate the <hi rend="fc">CD</hi>–<hi rend="fc">DSD</hi> phenotype fully or partially, suggesting the existence of an unusually large <hi rend="italic">cis</hi>‐regulatory control region. <hi rend="fc">P</hi>ierre <hi rend="fc">R</hi>obin sequence (<hi rend="fc">PRS</hi>) is a craniofacial disorder that is frequently an endophenotype of <hi rend="fc">CD</hi> and a locus for isolated <hi rend="fc">PRS</hi> at ∼1.2–1.5 Mb upstream of <hi rend="italic"><hi rend="fc">SOX</hi>9</hi> has been previously reported. The craniofacial regulatory potential within this locus, and within the greater genomic domain surrounding <hi rend="italic"><hi rend="fc">SOX</hi>9</hi>, remains poorly defined. We report two novel deletions upstream of <hi rend="italic"><hi rend="fc">SOX</hi>9</hi> in families with <hi rend="fc">PRS</hi>, 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 <hi rend="italic"><hi rend="fc">SOX</hi>9</hi> locus, which were validated in transgenic reporter mice and zebrafish. Notably, some of the functionally validated elements fall within the <hi rend="fc">PRS</hi> deletions. These studies suggest that multiple noncoding elements contribute to the craniofacial regulation of <hi rend="italic"><hi rend="fc">SOX</hi>9</hi> expression, and that their disruption results in <hi rend="fc">PRS</hi>.</p></abstract><abstract xml:lang="en" style="graphical" xml:id="humu22606-abs-0001"><p>The craniofacial regulatory potential of non‐coding DNA upstream of <hi rend="italic">SOX9</hi> has not been fully mapped. ChIP‐Seq analysis led to the identification of candidate <hi rend="italic">SOX9</hi> craniofacial enhancers. In transgenic zebrafish embryos, one of these elements, peak 17, drove expression of a GFP reporter gene in the pharyngeal arches. This element falls with deletions observed in Pierre Robin sequence (PRS) patients; loss of the element in these patients may result in abnormal expression of <hi rend="italic">SOX9</hi>, leading to the craniofacial phenotype of PRS.
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E‐mail: <email>chris.gordon@inserm.fr</email> or <email>stanislas.lyonnet@inserm.fr</email></correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:HUMU.HUMU22606.pdf"></link></linkGroup></publicationMeta><contentMeta><titleGroup><title type="main">Identification of Novel Craniofacial Regulatory Domains Located far Upstream of <i><fc>SOX</fc>9</i> and Disrupted in Pierre Robin Sequence</title></titleGroup><creators><creator xml:id="humu22606-cr-0001" creatorRole="author" affiliationRef="#humu22606-aff-0001" corresponding="yes"><personName><givenNames>Christopher T.</givenNames><familyName>Gordon</familyName></personName></creator><creator xml:id="humu22606-cr-0002" creatorRole="author" affiliationRef="#humu22606-aff-0002 #humu22606-aff-0003"><personName><givenNames>Catia</givenNames><familyName>Attanasio</familyName></personName></creator><creator xml:id="humu22606-cr-0003" creatorRole="author" affiliationRef="#humu22606-aff-0004"><personName><givenNames>Shipra</givenNames><familyName>Bhatia</familyName></personName></creator><creator xml:id="humu22606-cr-0004" creatorRole="author" affiliationRef="#humu22606-aff-0001 #humu22606-aff-0005"><personName><givenNames>Sabina</givenNames><familyName>Benko</familyName></personName></creator><creator xml:id="humu22606-cr-0005" creatorRole="author" affiliationRef="#humu22606-aff-0004"><personName><givenNames>Morad</givenNames><familyName>Ansari</familyName></personName></creator><creator xml:id="humu22606-cr-0006" creatorRole="author" affiliationRef="#humu22606-aff-0006"><personName><givenNames>Tiong Y.</givenNames><familyName>Tan</familyName></personName></creator><creator xml:id="humu22606-cr-0007" creatorRole="author" affiliationRef="#humu22606-aff-0001 #humu22606-aff-0007"><personName><givenNames>Arnold</givenNames><familyName>Munnich</familyName></personName></creator><creator xml:id="humu22606-cr-0008" creatorRole="author" affiliationRef="#humu22606-aff-0002 #humu22606-aff-0008"><personName><givenNames>Len A.</givenNames><familyName>Pennacchio</familyName></personName></creator><creator xml:id="humu22606-cr-0009" creatorRole="author" affiliationRef="#humu22606-aff-0009"><personName><givenNames>Véronique</givenNames><familyName>Abadie</familyName></personName></creator><creator xml:id="humu22606-cr-0010" creatorRole="author" affiliationRef="#humu22606-aff-0010"><personName><givenNames>I. 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Laboratory</orgName><address><city>Berkeley</city><countryPart>California</countryPart></address></affiliation><affiliation xml:id="humu22606-aff-0003" countryCode="CH"><orgDiv>Center for Integrative Genomics, Faculty of Biology and Medicine</orgDiv><orgName>University of Lausanne</orgName><address><city>Lausanne</city><country>Switzerland</country></address></affiliation><affiliation xml:id="humu22606-aff-0004" countryCode="GB"><orgDiv>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine</orgDiv><orgName>University of Edinburgh</orgName><address><city>Edinburgh</city><country>UK</country></address></affiliation><affiliation xml:id="humu22606-aff-0005"><orgDiv>Department of Structural and Chemical Biology</orgDiv><orgName>Icahn School of Medicine at Mount Sinai</orgName><address><city>New York City</city><countryPart>New York</countryPart></address></affiliation><affiliation xml:id="humu22606-aff-0006" countryCode="AU"><orgDiv>Victorian Clinical Genetics Services, Murdoch Children's Research Institute</orgDiv><orgName>Royal Children's Hospital</orgName><address><city>Melbourne</city><country>Australia</country></address></affiliation><affiliation xml:id="humu22606-aff-0007" countryCode="FR"><orgName>Hôpital Necker‐Enfants Malades AP‐HP</orgName><address><city>Paris</city><country>France</country></address></affiliation><affiliation xml:id="humu22606-aff-0008"><orgName>U.S. Department of Energy Joint Genome Institute</orgName><address><city>Walnut Creek</city><countryPart>California</countryPart></address></affiliation><affiliation xml:id="humu22606-aff-0009" countryCode="FR"><orgDiv>Service de Pédiatrie Générale, Université Paris Descartes</orgDiv><orgName>Hôpital Necker‐Enfants Malades</orgName><address><city>Paris</city><country>France</country></address></affiliation><affiliation xml:id="humu22606-aff-0010" countryCode="GB"><orgDiv>Human Genetics and Genomic Medicine, Faculty of Medicine</orgDiv><orgName>University of Southampton</orgName><address><city>Southampton</city><country>UK</country></address></affiliation><affiliation xml:id="humu22606-aff-0011" countryCode="FR"><orgDiv>Service de Génétique Médicale</orgDiv><orgName>CHU Charles Nicolle</orgName><address><city>Rouen</city><country>France</country></address></affiliation><affiliation xml:id="humu22606-aff-0012"><orgDiv>School of Natural Sciences</orgDiv><orgName>University of California</orgName><address><city>Merced</city><countryPart>California</countryPart></address></affiliation></affiliationGroup><keywordGroup type="author"><keyword xml:id="humu22606-kwd-0001"><i><fc>SOX</fc>9</i></keyword><keyword xml:id="humu22606-kwd-0002">craniofacial</keyword><keyword xml:id="humu22606-kwd-0003">enhancer</keyword><keyword xml:id="humu22606-kwd-0004">Pierre Robin</keyword><keyword xml:id="humu22606-kwd-0005">long‐range regulation</keyword><keyword xml:id="humu22606-kwd-0006">campomelic dysplasia</keyword></keywordGroup><fundingInfo><fundingAgency>ANR (EvoDevoMut, CRANIRARE, and IHU‐2010–001)</fundingAgency></fundingInfo><fundingInfo><fundingAgency>NHMRC Training Fellowship (#607431)</fundingAgency></fundingInfo><fundingInfo><fundingAgency>NIH</fundingAgency><fundingNumber>R01HG003988</fundingNumber><fundingNumber>U01DE020060</fundingNumber></fundingInfo><fundingInfo><fundingAgency>SNSF Advanced Researchers Fellowship; Department of Energy</fundingAgency><fundingNumber>DE‐AC02–05CH11231</fundingNumber></fundingInfo><supportingInformation><p>Disclaimer: Supplementary materials have been peer‐reviewed but not copyedited.</p><supportingInfoItem><mediaResource alt="supplementary_material" rendition="webOriginal" href="urn-x:wiley:10597794:media:humu22606:humu22606-sup-0001-supmat"></mediaResource><caption>Supporting Material</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main"><title type="main">ABSTRACT</title><p>Mutations in the coding sequence of <i><fc>SOX</fc>9</i> cause campomelic dysplasia (<fc>CD</fc>), a disorder of skeletal development associated with 46,<fc>XY</fc> disorders of sex development (<fc>DSD</fc>s). Translocations, deletions, and duplications within a ∼2 Mb region upstream of <i><fc>SOX</fc>9</i> can recapitulate the <fc>CD</fc>–<fc>DSD</fc> phenotype fully or partially, suggesting the existence of an unusually large <i>cis</i>‐regulatory control region. <fc>P</fc>ierre <fc>R</fc>obin sequence (<fc>PRS</fc>) is a craniofacial disorder that is frequently an endophenotype of <fc>CD</fc> and a locus for isolated <fc>PRS</fc> at ∼1.2–1.5 Mb upstream of <i><fc>SOX</fc>9</i> has been previously reported. The craniofacial regulatory potential within this locus, and within the greater genomic domain surrounding <i><fc>SOX</fc>9</i>, remains poorly defined. We report two novel deletions upstream of <i><fc>SOX</fc>9</i> in families with <fc>PRS</fc>, 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 <i><fc>SOX</fc>9</i> locus, which were validated in transgenic reporter mice and zebrafish. Notably, some of the functionally validated elements fall within the <fc>PRS</fc> deletions. These studies suggest that multiple noncoding elements contribute to the craniofacial regulation of <i><fc>SOX</fc>9</i> expression, and that their disruption results in <fc>PRS</fc>.</p></abstract><abstract xml:id="humu22606-abs-0001" type="graphical" xml:lang="en"><p>The craniofacial regulatory potential of non‐coding DNA upstream of <i>SOX9</i> has not been fully mapped. ChIP‐Seq analysis led to the identification of candidate <i>SOX9</i> craniofacial enhancers. In transgenic zebrafish embryos, one of these elements, peak 17, drove expression of a GFP reporter gene in the pharyngeal arches. This element falls with deletions observed in Pierre Robin sequence (PRS) patients; loss of the element in these patients may result in abnormal expression of <i>SOX9</i>, leading to the craniofacial phenotype of PRS.
<blockFixed type="graphic"><mediaResourceGroup><mediaResource alt="image" href="urn:x-wiley:10597794:media:humu22606:humu22606-gra-0001"></mediaResource></mediaResourceGroup></blockFixed></p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="humu22606-note-0001" numbered="no"><p>Communicated by Jacques S. Beckmann</p></note><note xml:id="humu22606-note-0003" numbered="no"><p>Contract grant sponsors: ANR (EvoDevoMut, CRANIRARE, and IHU‐2010–001); NHMRC Training Fellowship (#607431); NIH Grants (R01HG003988, U01DE020060); SNSF Advanced Researchers Fellowship; Department of Energy (Contract DE‐AC02–05CH11231).</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Identification of Novel Craniofacial Regulatory Domains Located far Upstream of SOX9 and Disrupted in Pierre Robin Sequence</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Identification of Novel Craniofacial Regulatory Domains Located far Upstream of SOX9 and Disrupted in Pierre Robin Sequence</title></titleInfo><name type="personal"><namePart type="given">Christopher T.</namePart><namePart type="family">Gordon</namePart><affiliation>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</affiliation><affiliation>E-mail: chris.gordon@inserm.fr</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Catia</namePart><namePart type="family">Attanasio</namePart><affiliation>Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California</affiliation><affiliation>Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Shipra</namePart><namePart type="family">Bhatia</namePart><affiliation>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sabina</namePart><namePart type="family">Benko</namePart><affiliation>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</affiliation><affiliation>Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York City</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Morad</namePart><namePart type="family">Ansari</namePart><affiliation>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Tiong Y.</namePart><namePart type="family">Tan</namePart><affiliation>Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Arnold</namePart><namePart type="family">Munnich</namePart><affiliation>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</affiliation><affiliation>Hôpital Necker‐Enfants Malades AP‐HP, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Len A.</namePart><namePart type="family">Pennacchio</namePart><affiliation>Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California</affiliation><affiliation>U.S. Department of Energy Joint Genome Institute, California, Walnut Creek</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Véronique</namePart><namePart type="family">Abadie</namePart><affiliation>Service de Pédiatrie Générale, Université Paris Descartes, Hôpital Necker‐Enfants Malades, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">I. Karen</namePart><namePart type="family">Temple</namePart><affiliation>Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alice</namePart><namePart type="family">Goldenberg</namePart><affiliation>Service de Génétique Médicale, CHU Charles Nicolle, Rouen, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Veronica</namePart><namePart type="family">van Heyningen</namePart><affiliation>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jeanne</namePart><namePart type="family">Amiel</namePart><affiliation>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</affiliation><affiliation>Hôpital Necker‐Enfants Malades AP‐HP, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David</namePart><namePart type="family">FitzPatrick</namePart><affiliation>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dirk A.</namePart><namePart type="family">Kleinjan</namePart><affiliation>MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Axel</namePart><namePart type="family">Visel</namePart><affiliation>Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California</affiliation><affiliation>U.S. Department of Energy Joint Genome Institute, Walnut Creek, California</affiliation><affiliation>School of Natural Sciences, University of California, California, Merced</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Stanislas</namePart><namePart type="family">Lyonnet</namePart><affiliation>Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, INSERM U1163, Paris, France</affiliation><affiliation>Hôpital Necker‐Enfants Malades AP‐HP, Paris, France</affiliation><affiliation>E-mail: chris.gordon@inserm.fr</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><dateIssued encoding="w3cdtf">2014-08</dateIssued><dateCreated encoding="w3cdtf">2014-06-21</dateCreated><dateCaptured encoding="w3cdtf">2014-02-21</dateCaptured><dateValid encoding="w3cdtf">2014-05-12</dateValid><copyrightDate encoding="w3cdtf">2014</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><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.</abstract><abstract type="graphical" lang="en">The craniofacial regulatory potential of non‐coding DNA upstream of SOX9 has not been fully mapped. ChIP‐Seq analysis led to the identification of candidate SOX9 craniofacial enhancers. In transgenic zebrafish embryos, one of these elements, peak 17, drove expression of a GFP reporter gene in the pharyngeal arches. This element falls with deletions observed in Pierre Robin sequence (PRS) patients; loss of the element in these patients may result in abnormal expression of SOX9, leading to the craniofacial phenotype of PRS.</abstract><note type="funding">ANR (EvoDevoMut, CRANIRARE, and IHU‐2010–001)</note><note type="funding">NHMRC Training Fellowship (#607431)</note><note type="funding">NIH - No. R01HG003988; No. U01DE020060; </note><note type="funding">SNSF Advanced Researchers Fellowship; Department of Energy - No. DE‐AC02–05CH11231; </note><subject><genre>keywords</genre><topic>SOX9</topic><topic>craniofacial</topic><topic>enhancer</topic><topic>Pierre Robin</topic><topic>long‐range regulation</topic><topic>campomelic dysplasia</topic></subject><relatedItem type="host"><titleInfo><title>Human Mutation</title></titleInfo><titleInfo type="abbreviated"><title>Human Mutation</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><note type="content"> Disclaimer: Supplementary materials have been peer‐reviewed but not copyedited.Supporting Info Item: Supporting Material - </note><subject><genre>article-category</genre><topic>Research Article</topic></subject><identifier type="ISSN">1059-7794</identifier><identifier type="eISSN">1098-1004</identifier><identifier type="DOI">10.1002/(ISSN)1098-1004</identifier><identifier type="PublisherID">HUMU</identifier><part><date>2014</date><detail type="volume"><caption>vol.</caption><number>35</number></detail><detail type="issue"><caption>no.</caption><number>8</number></detail><extent unit="pages"><start>1011</start><end>1020</end><total>10</total></extent></part></relatedItem><identifier type="istex">4B65229FDA86C14B5421D0AC7CAEB415D7BAB56F</identifier><identifier type="ark">ark:/67375/WNG-25S05PLL-5</identifier><identifier type="DOI">10.1002/humu.22606</identifier><identifier type="ArticleID">HUMU22606</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2014 Wiley Periodicals, Inc.© 2014 WILEY PERIODICALS, INC.</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-L0C46X92-X">wiley</recordContentSource></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/document/4B65229FDA86C14B5421D0AC7CAEB415D7BAB56F/metadata/json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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