Integration of microRNA miR-122 in hepatic circadian gene expression
- David Gatfield1,10,
- Gwendal Le Martelot1,8,
- Charles E. Vejnar2,3,8,
- Daniel Gerlach2,3,
- Olivier Schaad4,
- Fabienne Fleury-Olela1,
- Anna-Liisa Ruskeepää5,
- Matej Oresic5,
- Christine C. Esau6,
- Evgeny M. Zdobnov2,3,7 and
- Ueli Schibler1,9
- 1Department of Molecular Biology, Sciences III, University of Geneva, 30, CH-1211 Geneva, Switzerland;
- 2Department of Genetic Medicine and Development, University of Geneva Medical School, CH-1211 Geneva, Switzerland;
- 3Swiss Institute of Bioinformatics, CH-1211 Geneva, Switzerland;
- 4Genomics Platform, University of Geneva Medical School, CH-1211 Geneva, Switzerland;
- 5VTT Technical Research Centre of Finland, FI-02044 VTT, Finland;
- 6Regulus Therapeutics, Carlsbad, California 92008, USA;
- 7Imperial College London, SW7 2AZ London, United Kingdom
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↵8 These authors contributed equally to this work.
Abstract
In liver, most metabolic pathways are under circadian control, and hundreds of protein-encoding genes are thus transcribed in a cyclic fashion. Here we show that rhythmic transcription extends to the locus specifying miR-122, a highly abundant, hepatocyte-specific microRNA. Genetic loss-of-function and gain-of-function experiments have identified the orphan nuclear receptor REV-ERBα as the major circadian regulator of mir-122 transcription. Although due to its long half-life mature miR-122 accumulates at nearly constant rates throughout the day, this miRNA is tightly associated with control mechanisms governing circadian gene expression. Thus, the knockdown of miR-122 expression via an antisense oligonucleotide (ASO) strategy resulted in the up- and down-regulation of hundreds of mRNAs, of which a disproportionately high fraction accumulates in a circadian fashion. miR-122 has previously been linked to the regulation of cholesterol and lipid metabolism. The transcripts associated with these pathways indeed show the strongest time point-specific changes upon miR-122 depletion. The identification of Pparβ/δ and the peroxisome proliferator-activated receptor α (PPARα) coactivator Smarcd1/Baf60a as novel miR-122 targets suggests an involvement of the circadian metabolic regulators of the PPAR family in miR-122-mediated metabolic control.
Keywords
Footnotes
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↵9 Corresponding authors.
E-MAIL ueli.schibler{at}unige.ch; FAX 41-22-3796868.
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↵10 E-MAIL david.gatfield{at}unige.ch; FAX 41-22-3796868.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1781009.
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Supplemental material is available at http://www.genesdev.org.
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- Received January 12, 2009.
- Accepted April 20, 2009.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press