Tiny molecules called microRNAs, only 19 to 21 nucleotides in length, are able to effectively silence sometimes large sets of genes. They do this by specifically binding to and neutralizing another form of RNA called messenger RNA, responsible for conveying the information from genes to the cellular machinery that uses that information to create proteins, the building blocks of the body. Several hundred species of microRNAs have been identified to date, and increasingly they are being seen as vitally important players in regulating the genome.
Now, a new study led by researchers at The Wistar Institute shows that these microRNAs can undergo a kind of molecular editing with significant physiological consequences. A single substitution in their sequence can redirect these microRNAs to target and silence entirely different sets of genes from their unedited counterparts. Further, errors in the editing can lead to serious health problems. The team's findings appear in the February 23 issue of Science.
"What we found was that, in certain cases, edited versions of these microRNAs are being produced that differ from the unedited versions by only a single nucleotide change," says Kazuko Nishikura, Ph.D., a professor in the Gene Expression and Regulation Program at Wistar and senior author on the study. "These edited microRNAs are not encoded in the DNA, which means that at least two versions can being produced by one gene. This was not anticipated - it was something really new.
"Looking more closely, we realized that the substitution we'd identified occurred in a particularly critical region of the molecule, the first 7 or 8 nucleotides - out of a total of only 19 or 21 - that define the molecule's target specificity. This suggested that the change might well redirect these edited microRNAs to silence entirely different sets of genes from the unedited versions."
Using bioinformatics tools to compare the unedited and edited versions of only one species of microRNA against data banks of known gene sequences, the scientists identified two different groups of about 80 genes each likely to be targeted by the two versions of the molecule. They then selected three genes from each group for a closer look, testing to see whether their expression was in fact altered, up or down, by the microRNAs. It was.