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.
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We thank F. Camargo, C. Jan, J. Kim and C. Petersen for advice and discussions, R. Green and O. Rissland for comments on the manuscript, and the Whitehead Institute’s Genome Technology Core for sequencing and microarray profiling. This work was supported by grants from the NIH (D.P.B. and J.S.W.). H.G. was supported by the Agency for Science, Technology and Research, Singapore. N.T.I. was supported by a Ruth L. Kirschstein National Research Service Award (GM080853). D.P.B and J.S.W. are investigators of the Howard Hughes Medical Institute.
The authors declare no competing financial interests.
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Guo, H., Ingolia, N., Weissman, J. et al. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466, 835–840 (2010). https://doi.org/10.1038/nature09267
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