Rather than coding for proteins, miRNAs decrease protein levels by binding to their mRNA targets. Since their discovery in worms, researchers have wondered whether miRNAs simply fine-tune the genome's work or have large-scale effects of their own.
The first reports of mice lacking specific miRNAs suggest their effects are wide and strong. Antony Rodriguez, Allan Bradley (Sanger Institute, London, UK), and colleagues knocked out the gene coding for miR-155, which is active in the immune system and is up-regulated in lymphomas. The mice had defective T cell responses, were unable to fight off infection, and displayed lung tissue scarring seen in autoimmune diseases.
The same miRNA was also deleted by To-Ha Thai, Klaus Rajewsky (Harvard Medical School, Boston, MA), and colleagues. They found that these mice also had B cell defects. In normal animals, antigen-activated B cells proliferate in the germinal centers (GCs), which generate high-affinity antibodies and control immune memory. But these GC reactions were blunted in the knockouts, whose B cells failed to produce the necessary cytokines. Overexpressing miR-155, in contrast, enhanced the GC reaction.
Moving out of immunity and into the heart, Yong Zhao, Deepak Srivastava (Gladstone Institutes and University of California, San Francisco, CA), and colleagues knocked out miR-1-2, a regulator of cardiogenesis. The gene is one of two that encode identical mature miRNAs, yet even just cutting total miR-1 levels in half produced errors in cell cycle regulation and electroconductance in heart cells. The group found that the target mRNA's secondary structure must be open enough for the miRNA to attach. “If you imagine the mRNA balled up, even if there's great sequence matching, [the miRNA] can't get to it,” says Srivastava.
As additional knockouts emerge, in vivo studies will clarify which miRNAs have subtle or bold effects, the researchers note. The fact that individual miRNAs have grand effects puts them on the radar as a major regulatory system, Rajewsky says. “Somehow we've all mainly been thinking about transcription factors.”