Integration of microRNA miR-122 in hepatic circadian gene expression

  1. David Gatfield1,10,
  2. Gwendal Le Martelot1,8,
  3. Charles E. Vejnar2,3,8,
  4. Daniel Gerlach2,3,
  5. Olivier Schaad4,
  6. Fabienne Fleury-Olela1,
  7. Anna-Liisa Ruskeepää5,
  8. Matej Oresic5,
  9. Christine C. Esau6,
  10. Evgeny M. Zdobnov2,3,7 and
  11. Ueli Schibler1,9
  1. 1Department of Molecular Biology, Sciences III, University of Geneva, 30, CH-1211 Geneva, Switzerland;
  2. 2Department of Genetic Medicine and Development, University of Geneva Medical School, CH-1211 Geneva, Switzerland;
  3. 3Swiss Institute of Bioinformatics, CH-1211 Geneva, Switzerland;
  4. 4Genomics Platform, University of Geneva Medical School, CH-1211 Geneva, Switzerland;
  5. 5VTT Technical Research Centre of Finland, FI-02044 VTT, Finland;
  6. 6Regulus Therapeutics, Carlsbad, California 92008, USA;
  7. 7Imperial College London, SW7 2AZ London, United Kingdom
    1. 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.

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