RBM20 Regulates Circular RNA Production From the Titin Gene

Rationale:RNA-binding motif protein 20 (RBM20) is essential for normal splicing of many cardiac genes, and loss of RBM20 causes dilated cardiomyopathy. Given its role in splicing, we hypothesized an important role for RBM20 in forming circular RNAs(circRNAs), a novel class of noncoding RNA molecules. Objective:To establish the role of RBM20 in the formation of circRNAs in the heart. Methods and Results:Here, we performed circRNA profiling on ribosomal depleted RNA from human hearts and identified the expression of thousands of circRNAs, with some of them regulated in disease. Interestingly, we identified 80 circRNAs to be expressed from the titingene, a gene that is known to undergo highly complex alternative splicing. We show that some of these circRNAs are dynamically regulated in dilated cardiomyopathybut not in hypertrophic cardiomyopathy. We generated RBM20-null mice and show that they completely lack these titincircRNAs. In addition, in a cardiac sample from an RBM20 mutation carrier, titincirc...