Integration of microRNA miR-122 in hepatic circadian gene expression.
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.
Gatfield
David
D
Department of Molecular Biology, Sciences III, University of Geneva, Geneva, Switzerland. david.gatfield@unige.ch
Le Martelot
Gwendal
G
Vejnar
Charles E
CE
Gerlach
Daniel
D
Schaad
Olivier
O
Fleury-Olela
Fabienne
F
Ruskeepää
Anna-Liisa
AL
Oresic
Matej
M
Esau
Christine C
CC
Zdobnov
Evgeny M
EM
Schibler
Ueli
U
D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016678:Genome / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D020411:Oligonucleotide Array Sequence Analysis; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013997:Time Factors
D004268:DNA-Binding Proteins; D035683:MicroRNAs; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear