Biological principles of microRNA-mediated regulation: shared themes amid diversity

Abstract

MicroRNAs (miRNAs) are ∼22-nucleotide regulatory RNAs derived from endogenous transcripts containing inverted repeats. Their predominant function is to repress the activity of cellular target transcripts. In plants, most miRNAs are highly complementary to their targets and can cleave them; however, plant miRNAs can also inhibit the translation of highly complementary targets. In animals, miRNAs identify most of their targets through Watson–Crick complementary pairing (nucleotides 2–8 of the miRNA (the 'seed') pair with the target), and induce target destabilization and/or translational inhibition. The phenotypic requirements of most plant miRNAs, along with at least some animal miRNAs, seem to be mediated by the strong repression of one or a few important targets. For such miRNA genetic switches, the loss of miRNA-mediated regulation of individual target genes can lead to morphological or behavioural abnormalities. The regulation of a target by a miRNA could be relatively subtle and still have a substantial phenotypic impact, if the modulation of the target over a narrow range alters the target's output. Targets regulated in this manner include 'tuning', 'thresholding' and 'de-noising' targets. Conserved seven-nucleotide-seed matches, along with transcriptome and proteome analyses, have revealed that animal miRNAs have many (often hundreds) of targets. This might allow miRNAs to have a broad impact on the spatial or temporal identity of a cell. In other cases, however, most of these target interactions might be of minimal detectable consequence; detailed genetic studies are required to distinguish these possibilities. There is evidence, mostly from animals, that miRNA-mediated repression is reversible. Therefore, antagonizing miRNA activity allows the reuse of repressed target messages under conditions in which this is desirable. miRNA dysfunction may contribute to human disease in myriad ways. Ectopic miRNA activity or the loss of miRNA-binding sites could lead to abnormal levels of one or many transcripts. On the other hand, miRNA loss or gain of miRNA-mediated regulation could lead to the inappropriate silencing of one or many transcripts.