Abstract
Circular RNAs, a family of covalently circularized RNAs with tissue-specific expression, were recently demonstrated to play important roles in mammalian biology. Regardless of extensive research to predict, quantify, and annotate circRNAs, our understanding of their functions is still in its infancy. In this study, we developed a novel computational tool: Competing Endogenous RNA for INtegrative Annotations (Cerina), to predict biological functions of circRNAs based on the competing endogenous RNA model. Pareto Frontier Analysis was employed to integrate ENCODE mRNA/miRNA data with predicted microRNA response elements to prioritize tissue-specific ceRNA interactions. Using data from several circRNA-disease databases, we demonstrated that Cerina significantly improved the functional relevance of the prioritized ceRNA interactions by several folds, in terms of precision and recall. Proof-of-concept studies on human cancers and cardiovascular diseases further showcased the efficacy of Cerina on predicting potential circRNA functions in human diseases.
Highlights
Circular RNAs are a family of RNAs that form circular structures by joining the 3′ and 5′ ends covalently
CeRNA interactions that fall onto the first Pareto frontier represent the circRNA-miRNA interactions with the highest confidence, either based on expression data or binding data, or both (Fig. 1d)
Such procedure integratively re-prioritized a total of 1,540,275 competing endogenous RNA (ceRNA) interactions between 33,455 circRNAs and 606 miRNAs detected in 11 ENCODE tissues
Summary
Circular RNAs (circRNAs) are a family of RNAs that form circular structures by joining the 3′ and 5′ ends covalently. Among many putative mechanisms, such as interaction with RNA binding proteins (RBP), alternative splicing competition, posttranscriptional gene regulation, and protein coding, one of the most wellstudied circRNA functions is to act as the competing endogenous RNA (ceRNA) or miRNA “sponge”[3,7,8,9,10,11,12,13]. One notable ceRNA examples is CDR1as, a brain-enriched circRNA that is found to function as miRNA sponge for miR-718,19 in various human diseases, including colon cancer[20], gastric cancer[21], esophageal c ancer[22], and myocardial infarction[23]. In addition to the prominent role of CDR1as-miR7 sponging events in Alzheimer’s d isease[36,37], hundreds of circRNA were recently identified from multiple high-throughput studies to investigate circRNAmiRNA-mRNA interactions related to AD p athogenesis[38,39]. A user-friendly, web-based interface is made available for users to query a circRNA and retrieve its interacting miRNAs, their significant target genes, and the enriched biological functions and pathways
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