Tbx3-regulated Alternative RNA Processing in Cardiac Conduction System Development

Arrhythmias are a manifestation of acquired or congenital cardiac conduction system disease affecting at least 5% of the US population. They are an often lethal complication of myocardial infarction and cardiovascular disease, and the major cause of morbidity and death in congenital heart disease patients. Normal conduction sys-tem function is critical for prenatal survival. Tbx3 is a transcription factor expressed in the conduction system (CS)1. Development and homeostasis of the sinoatrial and atrioventricular nodes (SAN, AVN) are extremely sensitive to Tbx3: embryonic or adult deficiency in mice causes a variety of arrhythmias and sudden death2. Recent studies confirm the importance of TBX3 in human CS function3-7. We have discovered that Tbx3 regulates alternative splicing, transcription initiation and termination8,9. These alternative RNA processing events are the most important contributors to the complex transcriptomes required for tissue-specific gene expression10. Our preliminary data support our overall hypothesis that Tbx3-regulated alternative RNA processing is critical for CS development and homeostasis. All previous studies focused on Tbx3 as a transcriptional repressor; how Tbx3-regulated alternative RNA processing contributes to CS development and function is unknown. Our long term goal is to fill this gap to provide new targets for arrhythmia therapy and CS regeneration. The focus of this proposal is to discover Tbx3-regulated alternative RNAs relevant to SAN and AVN development, underlying regulatory mechanisms, and how human TBX3 mutations affect its RNA processing functions and protein interactions.