A tripartite structure, the complex nuclear receptor element (cNRE), is a c is-regulatory module of viral origin required for atrial chamber preferential gene expression
Year: 2021
Type: preprint
Abstract: Optimal cardiac function requires appropriate contractile proteins in each heart chamber. Atria require slow myosins to act as variable reservoirs, while ventricles demand fast myosin for swift pumping functions. Hence, myosin is under chamber-biased cis -regulatory control to achieve this functional distribution. Failure in proper regulation of myosin genes can lead to severe congenital heart dysfunction. The precise regulatory input leading to cardiac chamber-biased expression remains uncharted. To address this, we computationally and molecularly dissected the quail Slow Myosin Heavy Chain III (SMyHC III) promoter that drives specific gene expression to the atria to uncover the regulatory information leading to chamber expression and understand their evolutionary origins. We show that SMyHC III gene states are autonomously orchestrated by a complex nuclear receptor cis -regulatory element (cNRE), a 32- bp sequence with hexanucleotide binding repeats. Using in vivo transgenic assays in zebrafish and mouse models, we demonstrate that preferential atrial expression is achieved by the combinatorial regulatory input composed of atrial activation motifs and ventricular repression motifs. Through comparative genomics, we provide evidence that the cNRE emerged from an endogenous viral element, most likely through infection of an ancestral host germline. Our study reveals an evolutionary pathway to cardiac chamber-specific expression.
Authors: Luana Nunes Santos, Ângela Maria da Souza Costa, Martin Nikolov, Allysson Coelho Sampaio, Frank E. Stockdale, Gang F Wangø, Hozana Andrade Castillo, Mariana Bortoletto Grizante, Stefanie Dudczig, Michelle Vasconcelos, Nadia Rosenthal, Patricia Regina Jusuf, Paulo de Oliveira, Tatiana Guimarães de Freitas Matos, William Nikovits, Michael Schubert, Mirana Ramialison, José Xavier-Neto
Institutions: Universidade de São Paulo, Australian Regenerative Medicine Institute, Brazilian Center for Research in Energy and Materials, Brazilian Biosciences National Laboratory, Monash University, Faculdade Santa Marcelina, Stanford Medicine, Stanford University, The University of Melbourne, Jackson Laboratory, Imperial College London, Centre National de la Recherche Scientifique, Sorbonne Université, Laboratoire de Biologie du Développement de Villefranche-sur-Mer, Institut de la Mer de Villefranche, Universidade Federal do Ceará, Murdoch Children's Research Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Australian Government, University of Melbourne, Fundação de Amparo à Pesquisa do Estado de São Paulo, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico, State Government of Victoria, Centre National de la Recherche Scientifique, Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico, Australian Research Council, National Health and Medical Research Council, H2020 Marie Skłodowska-Curie Actions
OpenAlex ID: W3216129833