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PMID: 19901979 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Concordant regulation of translation and mRNA abundance for hundreds of targets of a human microRNA.

PLoS biology ·Vol. 7 ·No. 11 ·2009-11-00 ·Pages e1000238

Hendrickson DG, Hogan DJ, McCullough HL, Myers JW, Herschlag D, Ferrell JE, Brown PO

Abstract

MicroRNAs (miRNAs) regulate gene expression posttranscriptionally by interfering with a target mRNA's translation, stability, or both. We sought to dissect the respective contributions of translational inhibition and mRNA decay to microRNA regulation. We identified direct targets of a specific miRNA, miR-124, by virtue of their association with Argonaute proteins, core components of miRNA effector complexes, in response to miR-124 transfection in human tissue culture cells. In parallel, we assessed mRNA levels and obtained translation profiles using a novel global approach to analyze polysomes separated on sucrose gradients. Analysis of translation profiles for approximately 8,000 genes in these proliferative human cells revealed that basic features of translation are similar to those previously observed in rapidly growing Saccharomyces cerevisiae. For approximately 600 mRNAs specifically recruited to Argonaute proteins by miR-124, we found reductions in both the mRNA abundance and inferred translation rate spanning a large dynamic range. The changes in mRNA levels of these miR-124 targets were larger than the changes in translation, with average decreases of 35% and 12%, respectively. Further, there was no identifiable subgroup of mRNA targets for which the translational response was dominant. Both ribosome occupancy (the fraction of a given gene's transcripts associated with ribosomes) and ribosome density (the average number of ribosomes bound per unit length of coding sequence) were selectively reduced for hundreds of miR-124 targets by the presence of miR-124. Changes in protein abundance inferred from the observed changes in mRNA abundance and translation profiles closely matched changes directly determined by Western analysis for 11 of 12 proteins, suggesting that our assays captured most of miR-124-mediated regulation. These results suggest that miRNAs inhibit translation initiation or stimulate ribosome drop-off preferentially near the start site and are not consistent with inhibition of polypeptide elongation, or nascent polypeptide degradation contributing significantly to miRNA-mediated regulation in proliferating HEK293T cells. The observation of concordant changes in mRNA abundance and translational rate for hundreds of miR-124 targets is consistent with a functional link between these two regulatory outcomes of miRNA targeting, and the well-documented interrelationship between translation and mRNA decay.

MeSH Terms
Cell Line Eukaryotic Initiation Factors/metabolism Gene Expression Profiling Gene Expression Regulation Genes Genome, Human Humans MicroRNAs/metabolism Peptide Chain Initiation, Translational Protein Biosynthesis RNA Stability RNA, Messenger/metabolism Ribosomes/metabolism
Chemicals
Eukaryotic Initiation Factors MIRN124 microRNA, human MicroRNAs RNA, Messenger
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Hendrickson David G
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, USA.
Hogan Daniel J
McCullough Heather L
Myers Jason W
Herschlag Daniel
Ferrell James E
Brown Patrick O
Conflict of Interest

The authors have declared that no competing interests exist.

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Article Info
Journal
PLoS biology
Abbr.
PLoS Biol
ISSN
1545-7885
DOI
10.1371/journal.pbio.1000238
Published
2009-11-00
Epub
2009-00-10
Pages
e1000238
Language
English
Region
United States
NLM ID
101183755
PMCID
PMC2766070
Subset
IM
Grants
NCI NIH HHS · R01 CA077097 · United States
NCI NIH HHS · T32 CA009151 · United States
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · GM46383 · United States
NIGMS NIH HHS · R01 GM046383 · United States
NCI NIH HHS · R01 CA77097-08 · United States
NHGRI NIH HHS · T32 HG000044 · United States
NHGRI NIH HHS · K22 HG000044 · United States
NHGRI NIH HHS · HG00044 · United States
NCI NIH HHS · 2T32CA09151 · United States
External Links
PubMed source DOI: 10.1371/journal.pbio.1000238 PMC Full Text View journal details
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