A Tbx5-Atp2a2 gene regulatory network for cardiac rhythm - Resubmission 01

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Abstract Atrial Fibrillation (AF) is the most common cardiac arrhythmia and is associated with significant mortality and morbidity. AF is characterized by irregular heartbeats due to random electrical activity in the heart, and affects between 3-5 million individuals in the United States. The clinical and interventional therapies have moderate efficacy and are associated with serious side effects. There is a genetic component to an individual's predisposition for AF that is not fully understood. Therefore, our laboratory is particularly interested in understanding the genetic basis for cardiac arrhythmias, particularly through the identification of relevant gene regulatory networks involved in adult cardiac rhythm. Our lab has found that the deletion of Tbx5 from the adult mouse heart leads to spontaneous AF, therefore establishing the importance of the T-box transcription factor in maintaining atrial rhythm. The deep sequencing of polyA-depleted RNA from wild-type and TBX5-KO left atria identified candidate transcription factor dependent cis-regulatory elements (CREs) for calcium handling genes, including Atp2a2, which were validated in an in vitro luciferase response assay. We are also interested in elucidating the requirement of the ncRNA associated with this CRE. We hypothesize that the Tbx5-dependent ncRNA-defined CRE at Atp2a2, and the ncRNA itself, are required for Atp2a2 expression and cellular calcium homeostasis. Defining these cardiac rhythm regulatory networks may aid in the identification of individuals at risk for arrhythmia, and provide insight into new therapeutic discovery.