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Mammalian microRNAs predominantly act to decrease target mRNA levels

Nature volume 466, pages 835–840 (2010)Cite this article

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Abstract

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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Figure 1: Ribosome profiling in human cells captured features of translation.
Figure 2: MicroRNAs downregulated gene expression mostly through mRNA destabilization, with a small effect on translational efficiency.
Figure 3: Ribosome changes from miRNA targeting corresponded to mRNA changes.
Figure 4: Ribosome and mRNA changes were uniform along the length of the ORFs.

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Gene Expression Omnibus

Data deposits

Small-RNA sequencing data and array data were deposited in the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE22004.

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Acknowledgements

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.

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Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, Cambridge, 02142, Massachusetts, USA

    Huili Guo & David P. Bartel

  2. Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Huili Guo & David P. Bartel

  3. Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 94158, California, USA

    Nicholas T. Ingolia & Jonathan S. Weissman

  4. California Institute for Quantitative Biosciences, San Francisco, 94158, California, USA

    Nicholas T. Ingolia & Jonathan S. Weissman

Authors
  1. Huili Guo
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  2. Nicholas T. Ingolia
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  4. David P. Bartel
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Contributions

H.G. performed the experiments and analysed the data, with input from the other authors. H.G., J.S.W., and D.P.B. contributed to the design of the study, and all authors contributed to preparation of the manuscript.

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Correspondence to David P. Bartel.

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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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