Abstract
BackgroundHeart 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.ResultsOur 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.ConclusionsIn 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.
Highlights
Heart failure is a leading cause of human morbidity and mortality
By integrating the analysis of Circular RNA (circRNA) identified in human hearts with that of mouse and rat hearts in previous studies [26, 27, 29], we: (i) characterized the general features of circRNAs in human hearts and compared the identified circRNAs with circRNAs reported by previous studies and databases; (ii) determined the key circRNAs expressed in healthy hearts as defined by the top 30 most abundant circRNAs; (iii) identified circRNAs that are dysregulated in dilated cardiomyopathy (DCM) hearts; (iv) predicted the potential of high-confidence cardiac circRNAs to act as a sponge for previously identified heart disease-related miRNAs; Lastly, we identified a list of rt-circRNAs, especially those from the SCAF8 and TIAM2 gene loci that are dysregulated in DCM and show strong potential of being miRNA sponges
General features of circRNAs in both healthy and DCM human hearts We performed a de novo analysis of public RNA-seq data sets that were generated from left ventricular tissues obtained from 5 healthy individuals and 5 DCM patients [10]
Summary
Heart failure is a leading cause of human morbidity and mortality. 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. Heart failure (HF) is a leading cause of human morbidity and mortality worldwide. In addition to non-genetic causes, such as hypertension, inflammation, and toxins, genetic factors are increasingly recognized for their roles in HF susceptibility [3, 4]. Mutations in more than 100 genes have been linked to DCM [5]. These DCM relevant gene variants are only detected in ~ 37% of DCM patients [6]. The aberrant expression of different types of RNA transcripts, including those transcribed from protein coding genes [7,8,9], long noncoding genes [10, 11] and miRNAs [12,13,14], have been observed in DCM
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