microRNAs are pervasive post-transcriptional regulators of protein-coding genes in multicellular organisms. Two fundamentally different models have been proposed for the function of microRNAs in gene regulation. In the first model, microRNAs act as repressors, reducing protein concentrations by accelerating mRNA decay and inhibiting translation. In the second model, in contrast, the role of microRNAs is not to reduce protein concentrations per se but to reduce fluctuations in these concentrations. Here we present genome-wide evidence that mammalian microRNAs frequently function as noise controllers rather than repressors. Moreover, we show that post-transcriptional noise control has been widely adopted across species from bacteria to animals, with microRNAs specifically employed to reduce noise in regulatory and context-specific processes in animals. Our results substantiate the detrimental nature of expression noise, reveal a universal strategy to control it, and suggest that microRNAs represent an evolutionary innovation for adaptive noise control in animals.
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