Identification of miRNA Biogenesis Regulators and Activity Modulators
MicroRNAs (miRNAs) have emerged as key regulators of both normal and pathologic phenotypes, including cancer. Fine-grained regulation of their biogenesis, however, is still poorly understood and only a few of their key regulators have been characterized. In order to understand the extent and specificity of miRNA-biogenesis control, as well as the role of miRNA-biogenesis regulators in tumorigenesis and cancer progression, we set out to identify these regulators and profile their targets. We developed and experimentally validated MiRage, an algorithm for genome-wide inference of miRNA-biogenesis regulators. MiRage identifies biogenesis regulator by assessing the mutual information between mature miRNA expression and the expression of its transcription unit after conditioning for candidate biogenesis regulator expression. Thus, MiRage identifies genes whose expression correlates with deviations between mature miRNAs and their precursors. In addition to biogenesis, the miRNA targeting pathway is also extensively controlled with different mechanisms. Several regulators modulate miRNA activity by targeting miRISC or binding target mRNA. We developed an algorithm to perform genome-wide screens for modulators that affect miRNA activity from validated miRNA-target interactions. The predicted modulators were experimentally validated to regulate miRNA activity via post-transcriptional mechanism.