UCSF

The glucocorticoid receptor (GR) regulates numerous genes governing physiological processes including inflammation, metabolism, and development that may be influenced by the circadian clock, which itself can be entrained by GR. The molecular mechanism of this entrainment by GR has not been well described. Among the circadian genes whose transcriptional oscillation is affected by GR are the Period genes PER1, PER2 and PER3. To investigate the mechanism of clock entrainment, as well as gain further insight into gene-specific regulation by GR, we have examined the transcriptional dynamics and physiological effects of Period gene regulation by GR in both human and mouse primary cells and cell lines. Per2, a core clock protein which is transcriptionally induced by GR, has an effect on glucose homeostasis in a mouse model. Per3, which is transcriptionally repressed by GR, has an effect on adipogenesis in a mouse model. PER1 encodes a clock protein essential for maintenance of the transcriptional feedback loop that constitutes the basis of the circadian program. We found that PER1 is the circadian gene induced most rapidly and with the greatest magnitude upon addition of the GR agonist dexamethasone, and we found that PER1 induction appears to be necessary for circadian entrainment by GR.