Stress Regulated RNA Degradation in Cardiac Hypertrophy

PROJECT SUMMARY Cardiovascular disease progression includes the changes occurring at both cellular and molecular levels. The cardiac transcriptome remodeling, including both transcriptional and post-transcriptional regulation on mRNA largely contributes to the transcriptome complexity within the myocardium. Comparing to transcriptional regulation, the mRNA post-transcriptional regulation in heart remains understudied. Among the different RNA post-transcriptional regulation mechanisms, regulated degradation is an important part in maintaining RNA homeostasis. In our preliminary analysis, we have utilized a state-of-art sequencing approach- BRIC-Seq and have identified a global shift of RNA stability in hypertrophic cardiomyocytes. The genes that have changed stability include regulators for metabolism, inflammation, cardiac contractile function, and RNA processing. Further, we have discovered a novel RNA stability regulating complex involving the canonical RNA degradation helicase-Upf1 and a cardiac enriched RNA binding protein (RBP)-RBFox1c. Based on our extensive preliminary analysis, we hypothesized that Upf1-RBFox1c mediates stress regulated mRNA degradation (SRRD) in heart- while Upf1 serves as an RNA helicase for RNA degradation, RBFox1c provides target specificity by binding directly with the mRNA 3’UTR as an RNA binding protein. This proposal will combine both modern molecular sequencing technologies and mouse cardiac disease model to address the following specific aims: 1) Establish the contribution of Upf1 in stress regulated mRNA degradation in cardiomyocytes 2) Determine the role of RBFox1c in SRRD target specificity 3) Establish the functional significance of Upf1 mediated SRRD in cardiac hypertrophy. We believe our proposal will unfold an important layer of gene regulation in heart with critical implication in basic biology and yield novel insights on cardiac transcriptome remodeling where stress regulated RNA degradation can specifically target subpopulation of mRNA under both physiological and pathological conditions. Accomplishing the proposed study will also provide important evidence for the therapeutic potential of Upf1-RBFox1c complex in cardiac disease treatment.