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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
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E-mail addresses: Luana Nunes Santos: santosln89{at}gmail.com
Allysson Coelho Sampaio: allysson.sampaio{at}santamarcelina.edu.br
Ângela Maria da Souza Costa: angelamarsou{at}gmail.com
Frank E Stockdale: stockdale{at}stanford.edu
Hozana Andrade Castillo: hozana.castillo{at}monash.edu
Mariana Bortoletto Grizante: mari.grizante{at}gmail.com
Martin Nikolov: mnik0002{at}student.monash.edu
Michelle Vasconcelos: michellevasconcelos{at}gmail.com
Nadia Rosenthal: nadia.rosenthal{at}jax.org
Patricia Regina Jusuf: patricia.jusuf{at}unimelb.edu.au
Paulo de Oliveira: paulo.oliveira{at}lnbio.cnpem.br
Stefanie Dudczig: stefanie.dudczig{at}unimelb.edu.au
Tatiana Guimarães de Freitas Matos: tgfmatos{at}yahoo.com.br
William Nikovits JR: nikovits{at}comcast.net
Michael Schubert: michael.schubert{at}imev-mer.fr
José Xavier-Neto: josexavierneto{at}gmail.com