Cryptochromes mediate rhythmic repression of the glucocorticoid receptor

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

326 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)552-556
Number of pages5
JournalNature
Volume480
Issue number7378
DOIs
StatePublished - Dec 22 2011

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Cryptochromes mediate rhythmic repression of the glucocorticoid receptor'. Together they form a unique fingerprint.

Cite this