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Cryptochromes mediate rhythmic repression of the glucocorticoid receptor

2011; Nature Portfolio; Volume: 480; Issue: 7378 Linguagem: Inglês

10.1038/nature10700

1476-4687

Katja Lamia, Stephanie J. Papp, Ruth T. Yu, Grant D. Barish, N. Henriette Uhlenhaut, Johan W. Jonker, Michael Downes, Ronald M. Evans,

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Circadian co-regulators cryptochrome 1 and 2 are shown to alter globally the transcriptional response to glucocorticoids in mouse embryonic fibroblasts. Mammalian metabolism follows a regular 24-hour or circadian pattern. The major hormonal circuits, including that of the glucocorticoids, are linked to the circadian clock, but the nature of the linkage is poorly understood. This study shows that two clock co-regulators, cryptochromes 1 and 2, interact with the glucocorticoid receptor in a ligand-dependent manner to influence gene expression and normal metabolic homeostasis, and thus change the transcriptional response to glucocorticoids. Glucocorticoids are used clinically to suppress inflammation, but their nonspecific mode of action has been linked with various undesirable side effects. Altering the timing of treatment, or combining it with agents that specifically target the cryptochromes, may help to alleviate these side effects. Mammalian metabolism is highly circadian and major hormonal circuits involving nuclear hormone receptors display interlinked diurnal cycling1,2. 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.