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New Research Shows microRNAs Quiet Genomic Noise

NEW YORK (GenomeWeb) – While the physiological function of some microRNAs has been established, especially in cases where they strongly downregulate specific genes, the broader purpose of the small, non-coding RNAs has been unclear. New research published this week, however, indicates that miRNAs act as genomic noise dampeners, controlling variability in protein expression.

The ubiquity and conservation of miRNAs, combined with their tendency to only weakly repress the vast majority of their targets, has led some to speculate that they function to provide precision to gene expression across populations of cells.

In a study appearing in Science, a team led by researchers from the Massachusetts Institute of Technology and Humboldt University used a combination of mathematical modeling and synthetic genetics to demonstrate that miRNAs do, in fact, offer this kind of noise control.

"Previous work has hypothesized that miRNAs could reduce protein expression variability (noise) when their repressive post-transcriptional effects are antagonized by accelerated transcriptional dynamics," the team wrote. "However, because miRNA levels are themselves variable, one should expect the propagation of their fluctuations to introduce additional noise."

To test the effects of endogenous miRNAs, the investigators quantified protein levels and fluctuations in mouse embryonic stem cells using a dual fluorescent reporter system in which two different reporters are transcribed from a common bidirectional promoter. One of the reporters contained several variants and numbers of miRNA binding sites in its 3' UTR, and the scientists quantified single-cell fluorescence using a flow cytometer.

They examined the effects of miR-20a in the cells on a designed target site in the reporter. In cells with low expression of the reporter carrying a binding site for the miRNA, noise was reduced compared with a control. Noise was increased with high reporter expression.

Notably, the changes in noise were more pronounced when the miR-20a sites in the reporter were perfect targets or when there were multiple sites in the 3' UTR.

To explore the mechanism for these seemingly opposing effects on protein expression noise, the researchers built a mathematical model to break down total noise into intrinsic noise — the protein expression variability arising from the stochastic processes of protein production — and extrinsic noise — variability stemming from fluctuations propagating from external factors to the gene.

The model predicted opposite effects of miRNA regulation on the different types of noise, with an miRNA-regulated gene having reduced intrinsic noise compared with an unregulated gene at equal protein expression levels. Meanwhile, miRNA regulation was predicted to increase extrinsic noise.

Taken together, the model predicted that the net effect of decreased intrinsic and increased extrinsic noise would result in decreased total noise at low expression, but increased total noise at high expression.

To experimentally validate this prediction, the scientists modified their reporter system so that both reporters contained the same 3' UTRs and intracellular differences in their expression culd only result from processes individual to each gene, i.e. intrinsic noise.

"Comparing identical reporters both with and without miR-20a sites, we showed that miR-20a regulation reduced intrinsic noise, as compared to an unregulated construct," in line with what was predicted by the mathematical model, they wrote in Science. Higher reporter expression led to greater total noise, an increase due to additional extrinsic noise. Further experimentation demonstrated that genes regulated by multiple miRNAs undergo more pronounced noise reduction.

To determine how applicable their findings are in a natural setting, the researchers looked at expression for the full mouse genome and discovered that about 90 percent of all the genes are within the range of expression that would indicate they are subject to miRNA noise control.

Taken together, the findings suggest that miRNAs confer precision to protein expression, explaining the "commonly observed combinatorial targeting of endogenous genes by multiple miRNAs, as well as the preferential targeting of lowly expressed genes," the researchers concluded.