Integration of microRNA miR-122 in hepatic circadian gene expression

Genes Dev. 2009 Jun 1;23(11):1313-26. doi: 10.1101/gad.1781009.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • DNA-Binding Proteins
  • MicroRNAs
  • Nr1d1 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Peroxisome Proliferator-Activated Receptors
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear