Making the silencers: what makes microRNA biogenesis unique in human cells and why.

Our cells maintain their health during normal conditions (homeostasis) but also respond to stress (such as infection, or lack
of nutrients) by using remarkably sophisticated methods to determine “what” and “how much” they produce. MicroRNA (miRNA)-mediated silencing is an essential process involved gene expression regulation.

Changes in miRNA expression are inherently associated to disease. MiRNAs are generated through cleavage of long primary transcripts by two RNAse enzymes, DROSHA and DICER. This two-step process generates 21-24nt mature single stranded miRNAs. Remarkably, recent studies in our lab demonstrated that the whole of the miRNA generating machinery can be regulated during activation of human primary cells (Warner et al., Nucleic Acids Research, 2016). The potential to generate small silencing RNAs is conserved throughout evolution. However, the mammalian miRNA biogenesis machinery has some unique characteristics. One such feature is that DICER has two co-factors (instead of one or none), called TRBP and PACT.

This project will investigate how modifying the activities of these two proteins affects miRNA biogenesis in human cells and how this contributes to successful responses to metabolic or immunological stress. The student will work in a unique research environment in miRNA biology that bridges cellular function to protein structure. By the end of the project the student will be proficient in a wide range of molecular and cell biology methods that will allow them to address questions in the exciting and emerging field of non-coding RNA biology.