Computational prediction of microRNA targets remains a challenging problem. The existing rule-based, data-driven and expression profiling approaches to target prediction are mostly approached from the gene-level. The increasing availability of RNA-seq data provides a new perspective for microRNA target prediction on the isoform-level. We hypothesize that the splicing isoform is the ultimate effector in microRNA targeting and that the proposed isoform-level approach is capable of predicting non-dominant isoform targets as well as their targeting regions that are otherwise invisible to many existing approaches. To test the hypothesis, we used an iterative expectation maximization (EM) algorithm to quantify transcriptomes at the isoform-level. The performance of the EM algorithm in transcriptome quantification was examined in simulation studies using FluxSimulator. We used joint evidence from isoform-level down-regulation and seed enrichment to predict microRNA-155 targets. We validated our computational approach using results from 149 in-house performed in vitro 3′-UTR assays. We also augmented the splicing database using exon-exon junction evidence, and applied the EM algorithm to predict and quantify 1572 cell line specific novel isoforms. Combined with seed enrichment analysis, we predicted 51 novel microRNA-155 isoform targets. Our work is among the first computational studies advocating the isoform-level microRNA target prediction.
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