miRNA target enrichment analysis reveals directly active miRNAs in health and disease

microRNAs (miRNAs) are short non-coding regulatory RNA molecules. The activity of a miRNA in a biological process can often be reflected in the expression program that characterizes the outcome of the activity. We introduce a computational approach that infers such activity from high-throughput data using a novel statistical methodology, called minimum-mHG (mmHG), that examines mutual enrichment in two ranked lists. Based on this methodology, we provide a user-friendly web application that supports the statistical assessment of miRNA target enrichment analysis (miTEA) in the top of a ranked list of genes or proteins. Using miTEA, we analyze several target prediction tools by examining performance on public miRNA constitutive expression data. We also apply miTEA to analyze several integrative biology data sets, including a novel matched miRNA/mRNA data set covering nine human tissue types. Our novel findings include proposed direct activity of miR-519 in placenta, a direct activity of the oncogenic miR-15 in different healthy tissue types and a direct activity of the poorly characterized miR-768 in both healthy tissue types and cancer cell lines. The miTEA web application is available at http://cbl-gorilla.cs.technion.ac.il/miTEA/.