Cryptochromes mediate rhythmic repression of the glucocorticoid receptor

Mammalian metabolism is highly circadian and major hormonal circuits involving nuclear hormone receptors (NRs) display interlinked diurnal cycling(1,2). However, mechanisms that logically explain the coordination of NRs and the clock are poorly understood. Here we show that two circadian co-regulators, cryptochromes 1 (Cry1) and 2 (Cry2), interact with the glucocorticoid receptor (GR) in a ligand-dependent fashion and globally alter the transcriptional response to glucocorticoids in mouse embryonic fibroblasts (MEFs): Cry deficiency vastly decreases gene repression and approximately doubles the number of dexamethasone (Dex) induced genes suggesting that cryptochromes broadly oppose GR activation and promote repression. In mice, genetic loss of Cry1 and/or Cry2 resulted in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced suppression of the hypothalamic-pituitary-adrenal (HPA) axis coupled with increased glucocorticoid transactivation in the liver. Genomically, Cry1 and Cry2 associate with a glucocorticoid response element (GRE) in the phosphoenolpyruvate carboxykinase 1 (Pck1) promoter in a hormone-dependent manner, and Dex-induced transcription of pck1 was strikingly increased in Cry-deficient livers. These results reveal a specific mechanism through which cryptochromes couple the activity of clock and receptor target genes to complex genomic circuits underpinning normal metabolic homeostasis.