Cryptochromes mediate rhythmic repression of the glucocorticoid receptor (original) (raw)

Nature volume 480, pages 552–556 (2011)Cite this article

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Abstract

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.

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Gene Expression Omnibus

Data deposits

Microarray data are deposited in Gene Expression Omnibus under accession number GSE24469.

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Acknowledgements

We thank S. Kaufman for assistance with glucose tolerance tests, J. Alvarez for RNA sample preparation, H. Juguilon for luciferase assays, J. Vaughan for corticosterone and ACTH measurements, antigenic peptide design and peptide-KLH coupling reactions, H. Cho for sharing unpublished plasmids and R. Shaw for comments on the manuscript. This work was supported by National Institutes of Health grants DK057978 and DK062434 (to R.M.E.) and DK090188 (to K.A.L.), by support from the Glenn Foundation for Aging Research (to R.M.E. and K.A.L.), from the Helmsley Trust (to R.M.E.) and by a Merck fellowship from the Life Sciences Research Foundation (to K.A.L.).

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Author notes

  1. N. Henriette Uhlenhaut & Johan W. Jonker
    Present address: Present addresses: Max-Delbrueck-Centrum Fuer Molekulare Medizin, Genetics and Physiology, Berlin, 13125, Germany (N.H.U.); Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, The Netherlands(J.W.J.).,

Authors and Affiliations

  1. Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA,
    Katja A. Lamia, Ruth T. Yu, Grant D. Barish, N. Henriette Uhlenhaut, Johan W. Jonker, Michael Downes & Ronald M. Evans
  2. Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA,
    Katja A. Lamia & Stephanie J. Papp

Authors

  1. Katja A. Lamia
  2. Stephanie J. Papp
  3. Ruth T. Yu
  4. Grant D. Barish
  5. N. Henriette Uhlenhaut
  6. Johan W. Jonker
  7. Michael Downes
  8. Ronald M. Evans

Contributions

K.A.L. and R.E. conceived the project and designed the research. K.A.L., S.J.P., G.D.B. and N.H.U. performed the experiments. J.W.J. provided critical reagents. K.A.L. and R.T.Y. analysed the data. K.A.L. and R.M.E. wrote the paper. All authors edited the manuscript.

Corresponding authors

Correspondence toKatja A. Lamia or Ronald M. Evans.

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The authors declare no competing financial interests.

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Lamia, K., Papp, S., Yu, R. et al. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor.Nature 480, 552–556 (2011). https://doi.org/10.1038/nature10700

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Editorial Summary

Glucocorticoids take their tempo from cryptochromes

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.

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