Conserved enhancers control notochord expression of vertebrate Brachyury
Year: 2023
Type: article
Abstract: The cell type-specific expression of key transcription factors is central to development and disease. Brachyury/T/TBXT is a major transcription factor for gastrulation, tailbud patterning, and notochord formation; however, how its expression is controlled in the mammalian notochord has remained elusive. Here, we identify the complement of notochord-specific enhancers in the mammalian Brachyury/T/TBXT gene. Using transgenic assays in zebrafish, axolotl, and mouse, we discover three conserved Brachyury-controlling notochord enhancers, T3, C, and I, in human, mouse, and marsupial genomes. Acting as Brachyury-responsive, auto-regulatory shadow enhancers, in cis deletion of all three enhancers in mouse abolishes Brachyury/T/Tbxt expression selectively in the notochord, causing specific trunk and neural tube defects without gastrulation or tailbud defects. The three Brachyury-driving notochord enhancers are conserved beyond mammals in the brachyury/tbxtb loci of fishes, dating their origin to the last common ancestor of jawed vertebrates. Our data define the vertebrate enhancers for Brachyury/T/TBXTB notochord expression through an auto-regulatory mechanism that conveys robustness and adaptability as ancient basis for axis development.
Source: Nature Communications
Authors: Cassie L. Kemmler, Jana Smolikova, Hannah R. Moran, Brandon J. Mannion, Dunja Knapp, Fabian Lim, Anna Czarkwiani, Viviana Hermosilla Aguayo, Vincent Rapp, Olivia E. Fitch, Seraina Bötschi, Licia Selleri, Emma Farley, Ingo Braasch, Maximina Yun, Axel Visel, Marco Osterwalder, Christian Mosimann, Zbynek Kozmik, Alexa Burger
Institutions: University of Colorado Anschutz, Czech Academy of Sciences, Institute of Molecular Genetics, Lawrence Berkeley National Laboratory, University of California, Berkeley, Center for Regenerative Therapies Dresden, Technische Universität Dresden, University of California San Diego, University of California, San Francisco, University of Bern, Michigan State University, University of Zurich, Max Planck Society, Max Planck Institute of Molecular Cell Biology and Genetics, Physics of Life, University of California, Merced, Joint Genome Institute, University Hospital of Bern
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,290
Funders: National Science Foundation, U.S. Department of Health and Human Services, Children's Hospital Colorado, Additional Ventures, Deutsche Forschungsgemeinschaft, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Grantová Agentura České Republiky, Technische Universität Dresden, Zentrum für Regenerative Therapien Dresden, National Institutes of Health, Anschutz Medical Campus, University of Colorado, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Dental and Craniofacial Research
Awards: Regulatory dynamics of heart formation and in vivo cardiac reprogramming, G1760975967, G1794731937, Zelluläre und molekulare Grundlagen der de novo Regeneration des Thymus, G2784031255, EDGE FGT: Functional Genomics in Gar - Discovery Tools for Major Vertebrate Transitions, G3257704058, A Single-Cell Resolution Enhancer Atlas of Craniofacial Development, Deciphering the regulatory principles governing enhancer specificity, Investigating the regulation of chromatin associated proteins by intrinsically disordered regions, Chemical modulation of bromodomain function in development and disease, G660440469, Defining the developmental mechanisms of pericardium formation, Wechselspiel zwischen Regeneration und Alterung beim Axolotl, einer Art mit vernachlässigbarer Seneszenz, FZT 111: Zentrum für Regenerative Therapien Dresden (CRTD), In vivo Characterization of Regulatory Variant Pathogenicity in Congenital Heart Disease, Pbx-Directed Control of Cellular Behaviors that Drive Midface Morphogenesis, Predoctoral Training in the Genetics of Development, Disease and Regeneration, Functionally Assessing Transcriptional Enhancers In Vivo, Developmental causes of syndromic Thrombocytopenia and co-morbidities
OpenAlex ID: W4387737539