microRNAs: targeting seeds of destruction

A central dogma of biology goes like this: the DNA of genes is copied (‘transcribed’) to make messenger RNA (mRNA), and mRNA is then translated to make protein. Well, that’s what my textbooks used to say when I was a biology student.

This dogma remained unchallenged for decades, in fact until 1993, when Victor Ambros and colleagues identified a tiny RNA transcript in a worm. The worm was called C. elegans and the tiny transcript, lin-4. Without encoding any protein, this small RNA turned out to have a potent effect in the cells of  C. elegans – it could recognize and pair with  a complementary mRNA and prevent it from being translated into protein. Biologists call this effect ‘gene silencing‘.

It took several years before another of these tiny, silencing transcripts was found, and then the floodgates opened. In the years that followed, scientists discovered that these so-called microRNAs were present in lots of other animals and in plants too.

So how do these microRNAs work? Just 22 nucleotides long, these tiny transcripts control what proteins are made in a cell by preventing their translation from mRNAs. When a microRNA pairs with an mRNA, through complementary base pairing, the mRNA is destroyed or not translated.  But given how tiny microRNAs are, how do they find the right target to pair with and silence?  Early attempts to answer this question relied on computer programs but these tended to generate endless lists of targets, many of which turned out to be false.

So several years ago, Stephen Cohen and colleagues set about the laborious task of trying to answer this question. Their work culminated in a groundbreaking paper published in PLOS Biology, entitled Principles of MicroRNA–Target Recognition.

Using genetic tools and experimental approaches available to them in the model organism, Drosophila, Cohen and co discovered that miRNA targets can be divided into two overall categories: those that pair with just the 5′ end of microRNAs and those that additionally need to pair with its other end – the 3′ end.  Surprisingly, they also discovered that pairing with the 5′ end sometimes relied on so-called seed sites that consist of just seven or eight bases complementary to the microRNA 5′ end. The finding that so little sequence complementarity is needed revealed that microRNAs have many more target sites than had been previously imagined.  Indeed, Cohen and colleagues estimated that the Drosophila fly genome has about 100 sites for every microRNA in its genome.  That’s alot of targets, and this work hinted at the likelihood that microRNAs regulate many, many protein-coding genes by silencing their mRNAs.
With its discovery of how microRNAs accurately pair with their targets, this article had a far reaching impact on the field of microRNA biology and gene regulation. As PLOS Biology Editorial Board Member Avinash Bhandoola explains, this work offered“an important set of insights essential to the microRNA field”, including the development of computational tools better equipped to predict true microRNA targets.

Indeed, over the years, research on microRNAs has uncovered that these tiny regulators are involved in many key biological processes.

See the Tenth Anniversary PLOS Biology Collection or read the Biologue blog posts highlighting the rest of our selected articles.

Brennecke J, Stark A, Russell RB, & Cohen SM (2005). Principles of microRNA-target recognition. PLoS biology, 3 (3) PMID: 15723116