Cohen's group went looking for genes involved in growth control using a P-element–based overexpression screen. They found bantam, an miRNA, that when overexpressed causes a suppression of cell death and an increase in cell proliferation.
Using a computer program designed to identify miRNA targets, they found that bantam controls apoptosis by binding to hid mRNA, suppressing its translation and blocking its pro-death activity. They have not yet found the target mRNA involved in the proliferation portion of the bantam phenotype, but they have ruled out a number of the “usual suspects,” says Cohen. Identification of miRNA target genes has been a stumbling block thus far in the miRNA field. The group is currently working to further validate their computational method.
Xu et al., on the other hand, found mir14 and several other miRNAs in a large-scale genetic screen designed to identify suppressors of apoptosis. Out of 7,000 chromosomes screened over four years ago, they had ten hits, six of which were proteins and relatively easy to identify. However, the remaining four—all of which now appear to be miRNAs, including bantam and mir14—were initially intractable, says Hay.
He points out that the irony of this story is that the power of genetic screens is to let the organism tell you what is important and to show you novel things. Of course the team knew about miRNAs in C. elegans, but four years ago, they were still “stuck inside the protein box” and didn't seriously consider the possibility that their intractable mutants might be noncoding RNAs. That is, not until RNA silencing and miRNAs became a more familiar concept. “If there is a lesson to be learned,” says Hay, “it is to listen harder to what your screens are trying to tell you. This one did exactly what it was supposed to do, we just weren't listening as closely as we should have been.” ▪