MicroRNA Targeting

In animals, mRNAs are frequently targeted for repression by miRNAs. In collaboration with the David Bartel lab, we have used comparative genomics approaches to explore miRNA targeting, leading to development of the TargetScan and TargetScanS miRNA target prediction algorithms. These studies pointed to the critical importance for miRNA targeting of ‘seed match’ segments complementary to miRNA nucleotides 2-7, dubbed the miRNA ‘seed’ region. They also showed that at least one-third of human genes represent conserved targets of miRNAs. The predicted targets of some miRNA families have clear functional relatedness, and certain miRNAs and miRNA clusters appear to preferentially target tumor suppressor and other genes involved in growth control, supporting potential roles for miRNAs in cancer.

In addition to promoting translational inhibition of mRNAs, miRNAs often direct accelerated decay of targeted mRNAs, so that changes in mRNA as well as protein levels can be used as a readout of targeting. We are exploring targeting rules using available mRNA array data from miRNA/siRNA transfection experiments, as well as our own data from mouse cells following knockout of the miRNA processing enzyme, Dicer. These studies have led to the idea that there are different types of seed matches that confer different degrees of miRNA-directed repression. These studies have also found evidence that certain positions in the targeted mRNA may be recognized directly by protein components of the silencing complex rather than through pairing to the miRNA. The Dicer knockout data allow us to assess the degree to which mRNA targeting by endogenous miRNAs follows similar rules to targeting by exogenously added miRNAs or siRNAs. Current efforts are focused on identifying additional mRNA features that enhance or inhibit miRNA-directed targeting.