Abstract P3047: Alternative Splicing Networks During Postnatal Mouse Atria Development

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The heart is remodeled during the first four postnatal weeks to meet the increasing physical demands of the body. One driver of these changes is alternative splicing. Alternative splicing is an RNA processing mechanism that enables one gene to generate more than one transcript. Alternative splicing is ubiquitous, occurring in over 95% of human genes. The heart exhibits one of the most tissue specific and highly conserved alternative splicing programs, and mis-splicing is a hallmark of cardiovascular diseases. We previously identified extensive splicing changes during postnatal development in mouse ventricles; however, we still lack a molecular landscape of the developing atria. Here, we performed deep RNA-sequencing on mouse atria at four postnatal ages: P4.5, P10, P28, P90. We observed substantial changes in events that undergo alternative splicing of a single exon. These transitions are concentrated in the first four weeks (503 events between P4.5-P28; 83 events between P28-P90), suggesting they are functionally important for this developmental window. Gene Ontology (GO) analysis of the 503 events revealed pathways related to trafficking, intracellular architecture, and cardiac conduction. Notably, 287 (57%) of the alternative exons have sizes that are a multiple of three (in-frame), and the associated genes encode proteins that function in cell adhesion and extracellular matrix organization, while out-of-frame exons are present in genes encoding cell cycle proteins and transcription factors. We hypothesize that alternative splicing of in-frame exons imparts a novel functional role to the encoded protein, while splicing out-of-frame exons induces transcript instability and degradation. Alternative splicing is mainly regulated by RNA binding proteins (RBPs). We identified one upregulated RBP (RBFOX1) and two downregulated RBPs (FMR1, TIA1) between P4.5-P28, suggesting that these RBPs coordinate alternative splicing networks to promote atria development. Our efforts are focused on elucidating the mechanism by which these RBPs control alternative splicing in the developing atria as well as the functional consequences associated with each event. These findings will be fundamental to our understanding of cardiac development and disease.