Modulation of glucocorticoid receptor induction properties by core circadian clock proteins

Glucocorticoid (GC) plays important roles in diverse physiological processes including metabolism and immune functions. While circadian control of GC synthesis and secretion is relatively well appreciated, circadian control of GC action within target tissues remains poorly understood. Here, we demonstrate that CLOCK/BMAL1, the core circadian clock components, reduces maximal GR transactivation (A(max)) as well as efficacy (EC₅₀) by a novel mechanism that requires binding to DNA and transactivation of target genes. Accordingly, we observe that PER1 and CRY1, the primary targets of CLOCK/BMAL1 action, reduce maximal GR transactivation while not affecting the efficacy. Moreover, we observe hyper-activations of GRE-dependent transcription in BMAL1- or PERs-deficient MEFs. In addition, endogenous GC target genes expression negatively correlates with the CLOCK/BMAL1 activity. Considering that GC sensitivity is widely implicated in human health and diseases, these results provide valuable insights into plethora of GC-related physiology and pathology.