ComiR

MicroRNAs (miRNAs) are post-transcriptional regulators that bind to their target mRNAs through base complementarity. Predicting miRNA targets is a challenging task and various studies showed that existing algorithms suffer from high number of false predictions and low to moderate overlap in their predictions. Until recently, very few algorithms considered the dynamic nature of the interactions, including the effect of less specific interactions, the miRNA expression level, and the effect of combinatorial miRNA binding. Addressing these issues can result in a more accurate miRNA:mRNA modeling with many applications, including efficient miRNA-related SNP evaluation. We present a novel thermodynamic model based on the Fermi-Dirac equation that incorporates miRNA expression in the prediction of target occupancy and we show that it improves the performance of two popular single miRNA target finders. Modeling combinatorial miRNA targeting is a natural extension of this model. Two other algorithms show improved prediction efficiency when combinatorial binding models were considered. ComiR (Combinatorial miRNA targeting), a novel algorithm we developed, incorporates the improved predictions of the four target finders into a single probabilistic score using ensemble learning. Combining target scores of multiple miRNAs using ComiR improves predictions over the nave method for target combination. ComiR scoring scheme can be used for identification of SNPs affecting miRNA binding. As proof of principle, ComiR identified rs17737058 as disruptive to the miR-488-5p:NCOA1 interaction, which we confirmed in vitro. We also found rs17737058 to be significantly associated with decreased bone mineral density (BMD) in two independent cohorts indicating that the miR-488-5p/NCOA1 regulatory axis is likely critical in maintaining BMD in women. With increasing availability of comprehensive high-throughput datasets from patients ComiR is expected to become an essential tool for miRNA-related studies.[1]

ComiR is a web tool for combinatorial microRNA (miRNA) target prediction. Given an messenger RNA (mRNA) in human, mouse, fly or worm genomes, ComiR computes the potential of being targeted by a set of miRNAs, each of which can have zero, one or more targets on its 3'untranslated region. In determining the regulatory potential of an mRNA from a set of miRNAs, ComiR uses user-provided miRNA expression levels in a combination of appropriate thermodynamic modeling and machine learning techniques to make more accurate predictions. For each gene, ComiR returns the probability of being a functional target of a set of miRNAs, which depends on the relative miRNA expression levels. The tool provides a user-friendly interface to input a miRNA expression table containing many sample information and filter out the most relevant miRNAs. ComiR results can be downloaded or visualized on a table, which can then be used to select the most relevant targets and to compare the results obtained with different miRNA expression input. ComiR is freely available for academic use at http://www.benoslab.pitt.edu/comir/.[2]

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