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A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development.
Wilderman, Andrea; D'haene, Eva; Baetens, Machteld; Yankee, Tara N; Winchester, Emma Wentworth; Glidden, Nicole; Roets, Ellen; Van Dorpe, Jo; Janssens, Sandra; Miller, Danny E; Galey, Miranda; Brown, Kari M; Stottmann, Rolf W; Vergult, Sarah; Weaver, K Nicole; Brugmann, Samantha A; Cox, Timothy C; Cotney, Justin.
Afiliación
  • Wilderman A; Graduate Program UConn Health, Farmington, CT, USA.
  • D'haene E; Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
  • Baetens M; Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
  • Yankee TN; Graduate Program UConn Health, Farmington, CT, USA.
  • Winchester EW; Graduate Program UConn Health, Farmington, CT, USA.
  • Glidden N; University of Connecticut School of Dental Medicine, Farmington, CT, USA.
  • Roets E; Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT, USA.
  • Van Dorpe J; Department of Obstetrics, Women's Clinic, Ghent University Hospital, Ghent, Belgium.
  • Janssens S; Department of Pathology, Ghent University, Ghent University Hospital, Ghent, Belgium.
  • Miller DE; Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
  • Galey M; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Washington, WA, USA.
  • Brown KM; Seattle Children's Hospital, Seattle, WA, 98195, USA.
  • Stottmann RW; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98195, USA.
  • Vergult S; Brotman Baty Institute of Precision Medicine, University of Washington, Seattle, WA, 98195, USA.
  • Weaver KN; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Washington, WA, USA.
  • Brugmann SA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98195, USA.
  • Cox TC; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • Cotney J; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Nat Commun ; 15(1): 136, 2024 01 02.
Article en En | MEDLINE | ID: mdl-38167838
ABSTRACT
Craniofacial abnormalities account for approximately one third of birth defects. The regulatory programs that build the face require precisely controlled spatiotemporal gene expression, achieved through tissue-specific enhancers. Clusters of coactivated enhancers and their target genes, known as superenhancers, are important in determining cell identity but have been largely unexplored in development. In this study we identified superenhancer regions unique to human embryonic craniofacial tissue. To demonstrate the importance of such regions in craniofacial development and disease, we focused on an ~600 kb noncoding region located between NPVF and NFE2L3. We identified long range interactions with this region in both human and mouse embryonic craniofacial tissue with the anterior portion of the HOXA gene cluster. Mice lacking this superenhancer exhibit perinatal lethality, and present with highly penetrant skull defects and orofacial clefts phenocopying Hoxa2-/- mice. Moreover, we identified two cases of de novo copy number changes of the superenhancer in humans both with severe craniofacial abnormalities. This evidence suggests we have identified a critical noncoding locus control region that specifically regulates anterior HOXA genes and copy number changes are pathogenic in human patients.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Labio Leporino / Fisura del Paladar Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Pregnancy Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Labio Leporino / Fisura del Paladar Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Pregnancy Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido