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MicroRNAs ("miRNAs") are small post-transcriptional regulators. The function of these small RNAs in animals has been well characterized at a molecular level, but their role is less well known at the macroscopic scale: how could miRNAs have any biological function if they repress most of their targets less than 2-fold (while inter-individual gene expression fluctuation typically exceeds 2-fold, and is buffered by homeostatic mechanisms)?
According to the current dogma, each miRNA regulates tens or hundreds of targets, yet several observations suggest miRNAs have a much weaker impact on animal biology. We recently proposed an alternative hypothesis: most identified "targets" are not repressed enough by the miRNA to yield physiological consequences; these genes would rather act as competitive inhibitors, preventing the miRNA from interacting with its few, real targets. The only difference between real targets and competitive inhibitors would be the sensitivity of their biological activity to the modest repression guided by miRNAs. Hence the role of miRNAs in integrated phenomena should be assessed using a systems biology approach.
We are now testing directly the new hypothesis, assessing several of its predictions. We aim at providing the first quantitative analysis of miRNA action in vivo and an improvement in miRNA target identification (taking into account the extent of predicted repression and the robustness of affected biological pathways).
More generally, we are proposing a new vision of gene regulation: a regulatory target is not simply a gene that is affected by a regulatory pathway; it is a gene that is affected enough by the pathway - the extent of a measured regulation needs to be confronted to the robustness of biological systems to fluctuations.