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      Integration of microRNA miR-122 in hepatic circadian gene expression.

      Genes & development
      Animals, Circadian Rhythm, genetics, physiology, DNA-Binding Proteins, metabolism, Gene Expression Profiling, Gene Expression Regulation, Genome, Liver, Male, Mice, Mice, Inbred C57BL, MicroRNAs, Nuclear Receptor Subfamily 1, Group D, Member 1, Oligonucleotide Array Sequence Analysis, Peroxisome Proliferator-Activated Receptors, RNA, Messenger, Receptors, Cytoplasmic and Nuclear, Time Factors

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          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-ERBalpha 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 Pparbeta/delta and the peroxisome proliferator-activated receptor alpha (PPARalpha) 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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