MicroRNAs Exert Macro Control

A computer scan of thousands of genetic sequences indicates that more than 5000 human genes--around a fifth of the estimated total, and a third of those examined--are regulated by tiny stretches of RNA molecules called microRNAs (miRNAs). If the results hold up, these molecules may play a far greater role than expected in controlling how genes are expressed.

MiRNAs occur naturally in all sorts of animal and plant species, and hundreds have been discovered since the late 1990s. A single miRNA can ramp down expression of multiple genes--but the number of genes affected by known miRNAs hasn't been determined. Testing each of the roughly 22,000 mammalian genes against miRNAs one by one, to see which ones are controlled by the molecules, is inordinately painstaking and costly.

So molecular biologist David Bartel and Bartel's graduate student Benjamin Lewis, both at the Whitehead Institute for Biomedical Research and the Massachusetts Institute of Technology in Cambridge, along with MIT computational biologist Christopher Burge, decided to estimate the number computationally. Based on their previous work, they suspected that if a specific seven nucleotide stretch of an miRNA matched the sequence of a gene, that miRNA regulated that gene. (MiRNAs run about 21 nucleotides in length.)

To guard against "false positives," Bartel and Lewis focused mainly on genes that appeared in humans, mice, rats, dogs, and chickens. Only if the miRNA matched a sequence in all five species would it count towards the total. Running their computer algorithm, the biologists found that 5300 genes contained complementary sequences to an miRNA--suggesting that the miRNA could control that gene's expression, they report in the 14 January Cell. Lewis is now skimming through these genes to check their function; of those he's looked at so far, several are involved in growth and development, cell differentiation, cell death, and protecting against cancer.

"The number is stunning ... substantially more than anyone imagined," says Phillip Zamore, a molecular biologist at the University of Massachusetts Medical School in Worcester, of the 5300 figure. Still, he notes, it's a computational prediction, which "doesn't make it truth." While the miRNA field debates how much proof is needed to definitively match an miRNA to a gene, Zamore believes the search needs to be carried out with old-fashioned genetic methods, one gene at a time.

Related Sites
David Bartel's lab
Phillip Zamore's lab