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Loss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder.
Long, Hannah K; Osterwalder, Marco; Welsh, Ian C; Hansen, Karissa; Davies, James O J; Liu, Yiran E; Koska, Mervenaz; Adams, Alexander T; Aho, Robert; Arora, Neha; Ikeda, Kazuya; Williams, Ruth M; Sauka-Spengler, Tatjana; Porteus, Matthew H; Mohun, Tim; Dickel, Diane E; Swigut, Tomek; Hughes, Jim R; Higgs, Douglas R; Visel, Axel; Selleri, Licia; Wysocka, Joanna.
Afiliação
  • Long HK; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of M
  • Osterwalder M; Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
  • Welsh IC; Program in Craniofacial Biology, Department of Orofacial Sciences and Department of Anatomy, Institute of Human Genetics, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
  • Hansen K; Program in Craniofacial Biology, Department of Orofacial Sciences and Department of Anatomy, Institute of Human Genetics, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
  • Davies JOJ; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • Liu YE; Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Koska M; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Adams AT; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
  • Aho R; Program in Craniofacial Biology, Department of Orofacial Sciences and Department of Anatomy, Institute of Human Genetics, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
  • Arora N; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Ikeda K; Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
  • Williams RM; MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • Sauka-Spengler T; MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • Porteus MH; Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
  • Mohun T; The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA, UK.
  • Dickel DE; Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
  • Swigut T; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Hughes JR; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • Higgs DR; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Laboratory of Gene Regulation, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • Visel A; Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; US Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; School of Natural Sciences, University of California, Merced, Merced, C
  • Selleri L; Program in Craniofacial Biology, Department of Orofacial Sciences and Department of Anatomy, Institute of Human Genetics, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
  • Wysocka J; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of M
Cell Stem Cell ; 27(5): 765-783.e14, 2020 11 05.
Article em En | MEDLINE | ID: mdl-32991838
ABSTRACT
Non-coding mutations at the far end of a large gene desert surrounding the SOX9 gene result in a human craniofacial disorder called Pierre Robin sequence (PRS). Leveraging a human stem cell differentiation model, we identify two clusters of enhancers within the PRS-associated region that regulate SOX9 expression during a restricted window of facial progenitor development at distances up to 1.45 Mb. Enhancers within the 1.45 Mb cluster exhibit highly synergistic activity that is dependent on the Coordinator motif. Using mouse models, we demonstrate that PRS phenotypic specificity arises from the convergence of two mechanisms confinement of Sox9 dosage perturbation to developing facial structures through context-specific enhancer activity and heightened sensitivity of the lower jaw to Sox9 expression reduction. Overall, we characterize the longest-range human enhancers involved in congenital malformations, directly demonstrate that PRS is an enhanceropathy, and illustrate how small changes in gene expression can lead to morphological variation.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndrome de Pierre Robin / Crista Neural Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Cell Stem Cell Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndrome de Pierre Robin / Crista Neural Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Cell Stem Cell Ano de publicação: 2020 Tipo de documento: Article