title: Cryptochromes mediate rhythmic repression of the glucocorticoid receptor.
abstract: Mammalian metabolism is highly circadian and major hormonal circuits involving nuclear hormone receptors display interlinked diurnal cycling. However, mechanisms that logically explain the coordination of nuclear hormone receptors and the clock are poorly understood. Here we show that two circadian co-regulators, cryptochromes 1 and 2, interact with the glucocorticoid receptor in a ligand-dependent fashion and globally alter the transcriptional response to glucocorticoids in mouse embryonic fibroblasts: cryptochrome deficiency vastly decreases gene repression and approximately doubles the number of dexamethasone-induced genes, suggesting that cryptochromes broadly oppose glucocorticoid receptor activation and promote repression. In mice, genetic loss of cryptochrome 1 and/or 2 results in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced suppression of the hypothalamic-pituitary-adrenal axis coupled with increased glucocorticoid transactivation in the liver. Genomically, cryptochromes 1 and 2 associate with a glucocorticoid response element in the phosphoenolpyruvate carboxykinase 1 promoter in a hormone-dependent manner, and dexamethasone-induced transcription of the phosphoenolpyruvate carboxykinase 1 gene was strikingly increased in cryptochrome-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.
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA. klamia@scripps.edu
authors.forename: Katja A
authors.initials: KA
authors.lastname: Lamia
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Papp
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.forename: Grant D
authors.initials: GD
authors.lastname: Barish
authors.forename: N Henriette
authors.initials: NH
authors.lastname: Uhlenhaut
authors.forename: Johan W
authors.initials: JW
authors.lastname: Jonker
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D000818:Animals; D002940:Circadian Rhythm; D003345:Corticosterone / Q000097:blood; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D018149:Glucose Intolerance / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000097:blood / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
chemical_list: C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D003345:Corticosterone