MicroRNA plays role in gene regulation

Research conducted at the European Molecular Biology Laboratory has suggested that microRNA (miRNA) - small nucleic acid sequences of 20-24 nucleotides that do not code for proteins - in fact play a key role in gene expression.

The finding raises the possibility that interventions which target miRNA could help control the activity of genes and form a new means of treating diseases.

Simplified notions of the genetic machinery of the cell hold that 'DNA makes RNA makes protein,' according to the EMBL​ researchers, led by Stephen Cohen. This was challenged 20 years ago with the discovery of catalytic DNA, and revised again 10 years ago as the notion of RNA interference (RNAi) took hold.

Nevertheless, RNA molecules have largely been thought of as intermediaries between the information encoded in the genome and the proteins that do the work. However, "we know that small RNAs that do not encode proteins themselves can regulate messenger RNA molecules that do,"​ noted the EMBL team.

Cohen and colleagues are credited with the discovery of one miRNA gene, bantam​, in a nonprotein-coding region of the fruit fly genome. They found that bantam encodes a sequence that stimulates cell proliferation and prevents apoptosis.

miRNA sequences can bind to specific targets, which are then degraded rather than translated into protein. Hundreds of the small sequences have been identified in plants, worms, flies, mice, and humans, but their specific functions have remained elusive because it has been very difficult to identify their targets.

Until now, targets were known for only three animal miRNAs, a tiny tip of what most experts expect will be a vast iceberg of RNA-regulated genes. Cohen and his colleagues at the Heidelberg-based EMBL took a bioinformatics approach to identify additional targets in the fruit fly Drosophila melanogaster​, a commonly-used model for genetic research.

They started by determining features that were shared by the few previously validated targets of animal miRNAs and then systematically searched for similar features in the Drosophila​ genome databases. To reduce the rate of false-positives, Cohen and colleagues determined whether the target sequences were similar between two closely related fruit fly species, working on the assumption true miRNA targets would be evolutionary conserved.

Where the information was available, they also incorporated information from the partially completed mosquito genome sequence.

This resulted in lists of predicted targets for over 60 Drosophila​ microRNAs, which the authors ordered such that those targets that they considered most likely to be real were at the top. This strategy correctly identified all previously validated targets from a large database, and puts them near the top of the ordered lists. Moreover, Cohen and colleagues selected six additional predicted targets and were able to experimentally validate all of them.

This not only more than doubles the size of the iceberg's tip, but the fact that Cohen and colleagues publish their full lists and invite other researchers to check whether their favourite genes are likely to be miRNA targets, also suggests that we will soon get a better sense of what's under the water.

However, a number of challenges remain before miRNAs can emerge as drug targets. At present, no-one has been able to isolate a complex between an miRNA and its target in order to explore the mechanism of gene repression.

Also, in mammals there are often multiple versions of the same miRNA genes which makes them difficult to study by using knockout (gene deletion) approaches, and conventional in situ​ hybridisation experiments are unreliable as miRNAs are too short to generate a signal.