Identification of mechanism(s) of miRNA- mediated repression of translation

Recently, a completely new way of controlling gene expression has been identified. This has come to light after the discovery of a whole new class of genes comprising very small RNA molecules, that unlike most genes do not produce proteins. There are at least 800 of these small RNA molecules within the human genome which have different effects. They work by binding to the mRNA of other genes and inhibiting the target genes from being made into proteins. Each of these 800 small molecules is believed to interact with 100 other genes, thus adding to the complexity of the regulation of the human genome. Already it has become clear that malfunction of miRNA regulation is associated with a growing list of human disease, including: cancer; diabetes; and viral infections. In 2002 Science magazine called miRNA the breakthrough of the year and these small RNA molecular have been termed the 'Dark Matter of the cell'. At present there is great controversy within the scientific community over how these small RNA molecules repress gene expression. Laboratories around the world have shown conflicting data for how this repression mechanism functions, and have failed to reproduce each other's data. We have, for the first time, been able to shown both repression mechanisms operating and determined how these difference are occurring. We are now in a unique position to investigate the different mechanisms and to determine which genes are regulated by the different repression systems. This will lead to a great impact on the way in which we understand gene expression and the complexity of the human genome.

microRNAs comprise of 2-3% of the cellular genome and exert their phenotype influence via interacting with imperfect complementary to the 3`untranslated regions (UTR) of mRNAs. It has been suggested that between 74-92% of mRNAs are regulated by microRNAs. The mechanisms of regulation appear to occur primarily at the level of translation. However there is a dispute in the field about the mechanism(s) used to achieve miRNA-mediated repression with data from some laboratories suggesting a block at translation initiation whilst other data strongly showing a post-initiation inhibition. We have been able to show that the promoter element dictates whether the repression mechanisms occur at the level of initiation or post initiation. We are now in a unique position to investigate both the factors which mediate this types of regulation and which genes are controlled by the two different mechanisms.