RBM24-mediated biogenesis of circ23679 protects cardiomyocytes against apoptosis via sponging miR-15b-5p

Circular RNAs (circRNAs) have emerged as significant members of gene regulatory networks and play important roles in normal heart biology and cardiac diseases. RNA binding proteins (RBPs) are key regulatory factors in circRNA formation; however, the mechanisms by which RBP regulate circRNA production remain unclear. RNA binding motif protein 24 (RBM24) is essential for alternative splicing of genes related to cardiac function, and its loss leads to dilated cardiomyopathy and heart failure. In this study, we performed circRNA profiling on hearts from wild-type and Rbm24 knockout mice, identifying the differential expression of circRNAs. We demonstrated that RBM24 could directly bind to pre-mRNA, facilitating the inclusion of specific exons to provide a substrate for circ23679 production. Moreover, RBM24-regulated circRNA production depended on its phosphorylation status. Further, we showed that RBM24-mediated circ23679 acted as a sponge of miR-15b-5p, and a deficient in circ23679-mediated 'sponging events' could drive cardiac apoptosis. Conversely, circ23679 overexpression inhibited cardiac apoptosis and alleviated the disease phenotype in mouse models of heart failure. Thus, our study not only proposes a novel model in which RBPs provide the substrate for circRNA formation but also reveals that RBM24-dependent circRNA production is a crucial post-transcriptional regulatory circuit in cardiac pathogenesis.