The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors.
Mammalian circadian clocks provide a temporal framework to synchronize biological functions. To obtain robust rhythms with a periodicity of about a day, these clocks use molecular oscillators consisting of two interlocked feedback loops. The core loop generates rhythms by transcriptional repression via the Period (PER) and Cryptochrome (CRY) proteins, whereas the stabilizing loop establishes roughly antiphasic rhythms via nuclear receptors. Nuclear receptors also govern many pathways that affect metabolism and physiology. Here we show that the core loop component PER2 can coordinate circadian output with the circadian oscillator. PER2 interacts with nuclear receptors including PPARalpha and REV-ERBalpha and serves as a coregulator of nuclear receptor-mediated transcription. Consequently, PER2 is rhythmically bound at the promoters of nuclear receptor target genes in vivo. In this way, the circadian oscillator can modulate the expression of nuclear receptor target genes like Bmal1, Hnf1alpha, and Glucose-6-phosphatase. The concept that PER2 may propagate clock information to metabolic pathways via nuclear receptors adds an important facet to the clock-dependent regulation of biological networks.
Schmutz
Isabelle
I
Department of Medicine, Unit of Biochemistry, University of Fribourg, 1700 Fribourg, Switzerland.
Ripperger
Jürgen A
JA
Baeriswyl-Aebischer
Stéphanie
S
Albrecht
Urs
U
D056930:ARNTL Transcription Factors / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
D056930:ARNTL Transcription Factors; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D047493:PPAR alpha; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D005947:Glucose