Just when you think you’ve got a handle on microRNAs, they go and up their game—regulating other microRNAs to produce large effects. To be accurate, they’ve been doing this all along, but now a talented research crew at Wash U School of Medicine of medicine is on to their game and has shared their findings in Circulation Research.
“We had been interested for some time in how changes in single microRNAs could have large effects on the heart, considering that individual microRNAs only moderately suppress their targets,” says Scot Matkovich, who’s at the Center for Pharmacogenomics at the Washington University School of Medicine.
“The field has been aware for some time that microRNAs have many indirect effects,” he adds. “They’re integral members of a complex system, in which a change at one ‘node’ or signaling center leads to ripple effects through the system, and indirect effects on mRNA expression have certainly been observed previously. While it seems straightforward in hindsight, we don’t believe that anyone had systemically documented indirect effects of microRNAs on transcription of other noncoding RNAs before, including other microRNAs.”
miRNAs Regulating miRNAs
So, that’s just what they did. They overexpressed three microRNAs—miR-143, miR-378, and miR-499—in mouse hearts at levels similar to those in diseased human hearts to try to figure things out. Here’s some of what they found:
- Overexpressing miR-143 didn’t really have an effect on cardiac mRNA levels, but the other two did.
- Overexpression of miR-378 and miR-499 (both of which can modulate gene expression pathways) changed the expression of other microRNAs—but miR-143 overexpression didn’t have this effect.
- microRNA processing wasn’t affected by high levels of these three non-coding RNAs.
Matkovich says that, based on the study, at least part of the explanation as to why changes in single microRNAs can sometimes have such big effects “involves feedback on primary transcription of other microRNAs.
“So, we think that microRNAs amplify their effects by recruiting or regulating other microRNAs. It does add another layer of complexity to defining mechanisms of microRNA action, and should be relevant to systems other than the heart.
“I think one of the most surprising things about the work is how much of the effect of manipulating a single microRNA might depend on the secondarily recruited microRNAs (up to 30-50%),” he notes.
Learn more at Circulation Research, April 2013.