Genomic analysis of circular RNAs in heart

Background: Heart failure is a leading cause of human morbidity and mortality. Circular RNAs (circRNAs) are a newly discovered class of RNA that have been found to have important physiological and pathological roles. In the current study, we de novo analyzed existing whole transcriptome data from 5 normal and 5 dilated cardiomyopathy (DCM) human heart samples and compared the results with circRNAs that have been previously reported in human, mouse and rat hearts. Results: Our analysis identifies a list of cardiac circRNAs that are reliably detected in multiple studies. We have also defined the top 30 most abundant circRNAs in healthy human hearts which include some with previously unrecognized cardiac roles such as circHIPK3_11 and circTULP4_1. We further found that many circRNAs are dysregulated in DCM, particularly transcripts originating from DCM-related gene loci, such as TTN and RYR2. In addition, we predict the potential of cardiac circRNAs to sponge miRNAs that have reported roles in heart disease. We found that circALMS1_6 has the highest potential to bind miR-133, a microRNA that can regulate cardiac remodeling. Interestingly, we detected a novel class of circRNAs, referred to as read-though (rt)-circRNAs which are produced from exons of two different neighboring genes. Specifically, rt-circRNAs from SCAF8 and TIAM2 were observed to be dysregulated in DCM and these rt-circRNAs have the potential to sponge multiple heart disease-related miRNAs. Conclusions: In summary, this study provides a valuable resource for exploring the function of circRNAs in human heart disease and establishes a functional paradigm for identifying novel circRNAs in other tissues.