Mammalian microRNAs predominantly act to decrease target mRNA levels

MicroRNAs (miRNAs) are endogenous ∼22-nucleotide RNAs that mediate important gene-regulatory events by pairing to the mRNAs of protein-coding genes to direct their repression. Repression of these regulatory targets leads to decreased translational efficiency and/or decreased mRNA levels, but the relative contributions of these two outcomes have been largely unknown, particularly for endogenous targets expressed at low-to-moderate levels. Here, we use ribosome profiling to measure the overall effects on protein production and compare these to simultaneously measured effects on mRNA levels. For both ectopic and endogenous miRNA regulatory interactions, lowered mRNA levels account for most (≥84%) of the decreased protein production. These results show that changes in mRNA levels closely reflect the impact of miRNAs on gene expression and indicate that destabilization of target mRNAs is the predominant reason for reduced protein output. MicroRNA shoots messenger MicroRNAs — the ubiquitous, short noncoding RNAs that regulate gene expression — are known to affect the levels of both messenger RNA (mRNA) and protein. But because protein production is dependent on the presence of mRNA, it has been difficult to establish the relative contributions of microRNA-mediated mRNA cleavage versus translational repression. David Bartel and colleagues have now disentangled the two mechanisms, and, contrary to expectation, find that microRNAs act mainly by destabilizing target mRNAs, rather than by inhibiting their translation. These results suggest that a reassessment of many previous conclusions is in order. MicroRNAs are known to affect the levels of both messenger RNA (mRNA) and protein. But as protein production is dependent on the presence of mRNA, it was not clear what the relative contributions of microRNA-mediated mRNA cleavage and translational repression were. These authors have parsed out the two mechanisms, and unexpectedly find that microRNAs function primarily by affecting mRNA levels rather than their translation. This suggests a reassessment of many previous conclusions is necessary.