Integration of microRNA miR-122 in hepatic circadian gene expression

Gatfield; David, Gwendal Le Martelot, Charles E. Vejnar, Daniel Gerlach, Olivier Schaad, Fabienne Fleury-Olela, Anna-Liisa Ruskeepää, Matej Oresic, Christine C. Esau, Evgeny M. Zdobnov, Ueli Schibler (Corresponding Author)

    Research output: Contribution to journalArticleScientificpeer-review

    283 Citations (Scopus)

    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.
    Original languageEnglish
    Pages (from-to)1313-1326
    Number of pages14
    JournalGenes and Development
    Volume23
    Issue number11
    DOIs
    Publication statusPublished - 2009
    MoE publication typeA1 Journal article-refereed

    Keywords

    • Circadian
    • miRNA
    • miR-122
    • metabolism
    • clock
    • PPAR

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