Résumé
microRNAs (miRNAs) are major regulators of gene expression and thereby modulate many biological processes. Computational methods have been instrumental in understanding how miRNAs bind to mRNAs to induce their repression but have proven inaccurate. Here we describe a novel method that combines expression data from human and mouse to discover conserved patterns of expression between orthologous miRNAs and mRNA genes. This method allowed us to predict thousands of putative miRNA targets. Using the luciferase reporter assay, we confirmed 4 out of 6 of our predictions. In addition, this method predicted many miRNAs that act as expression enhancers. We show that many miRNA enhancer effects are mediated through the repression of negative transcriptional regulators and that this effect could be as common as the widely reported repression activity of miRNAs. Our findings suggest that the indirect enhancement of gene expression by miRNAs could be an important component of miRNA regulation that has been widely neglected to date. microRNAs are small RNA molecules that regulate gene expression by controlling the output of proteins and other RNAs. The exact mechanism through which a microRNA binds to its target and how this affects the target is still a subject of much debate. In this article, the authors sought to find a reverse approach to discover the impact of microRNAs on gene expression. Instead of searching for specific targets of a given microRNA, they searched for microRNA signatures: changes in the levels of microRNAs across multiple tissues that impacted significantly the levels of messenger gene expression in these same tissues. Because many core biological functions are conserved between human and mouse, the authors compared these microRNA signatures between these two species. They found that identical microRNA signatures between these organisms could effectively predict microRNA targets and could estimate the global impact of individual microRNAs on gene output. They further demonstrated that many microRNAs act as expression enhancers by inhibiting gene repressors.