Over the course of the current decade, microRNA-mediated regulation has been recognized as a major mechanism controlling gene expression at the post-transcriptional level. miRNAs regulate numerous and diverse aspects of biology, including development, differentiation, proliferation, metabolism and immunity. A single miRNA can regulate hundreds of genes and a gene can be regulated my multiple miRNAs. miRNAs suppress gene expression by binding to mature mRNA transcripts and promoting mRNA degradation, inhibiting translation or both. Identifying “true” targets still remains a challenge due to lack of perfect complementarity of binding of the miRNA to target mRNAs, resulting in the prediction of thousands of targets.
In this dissertation, we seek to use bioinformatics approaches to narrow down these target predictions and place them in specific biological contexts. We begin by building a gene annotation enrichment and visualization tool that can be used to characterize the functions of miRNA targets with respect to a number of functional features. We then use protein-protein interaction networks as a basis for miRNA target prioritization and identification of potential miRNA-regulated modules. We find that many of the central proteins in protein-protein interaction sub-networks of miRNA targets are known targets. We also find that modularity within a miRNA-regulated interactome could be biologically meaningful and could serve as a way to dissect the diversity of functions regulated by a miRNA. Looking at another aspect, we integrate miRNA and gene expression analyses to narrow down the target predictions. Using expression data from two diseases, we identify facets of miRNA involvement, some that are already known and others that are novel.
The results found here show the feasibility of our approaches to identify potentially important targets of miRNAs. Further extension and generalization of these approaches could equip researchers with useful tools for sifting through the considerable amounts of existing miRNA targets information.