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Cryptochromes mediate rhythmic repression of the glucocorticoid receptor

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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Figure 1: Cryptochromes interact with glucocorticoid receptor.
Figure 2: Cryptochromes modulate glucocorticoid-receptor-dependent transcription.
Figure 3: Cryptochromes interact with glucocorticoid receptor on chromatin to regulate pck1.
Figure 4: Genetic loss of cryptochromes alters physiology.

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Primary accessions

Gene Expression Omnibus

Data deposits

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

References

  1. Yang, X. et al. Nuclear receptor expression links the circadian clock to metabolism. Cell 126, 801–810 (2006)

    Article  CAS  Google Scholar 

  2. Green, C. B., Takahashi, J. S. & Bass, J. The meter of metabolism. Cell 134, 728–742 (2008)

    Article  CAS  Google Scholar 

  3. Weinberger, C. et al. Identification of human glucocorticoid receptor complementary DNA clones by epitope selection. Science 228, 740–742 (1985)

    Article  CAS  ADS  Google Scholar 

  4. Lonard, D. M. & O’Malley, B. W. The expanding cosmos of nuclear receptor coactivators. Cell 125, 411–414 (2006)

    Article  CAS  Google Scholar 

  5. De Bosscher, K., Vanden Berghe, W. & Haegeman, G. Cross-talk between nuclear receptors and nuclear factor kappaB. Oncogene 25, 6868–6886 (2006)

    Article  CAS  Google Scholar 

  6. Damiola, F. et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 14, 2950–2961 (2000)

    Article  CAS  Google Scholar 

  7. Lamia, K. A. et al. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326, 437–440 (2009)

    Article  CAS  ADS  Google Scholar 

  8. Asher, G. et al. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134, 317–328 (2008)

    Article  CAS  Google Scholar 

  9. Asher, G. et al. Poly(ADP-ribose) polymerase 1 participates in the phase entrainment of circadian clocks to feeding. Cell 142, 943–953 (2010)

    Article  CAS  Google Scholar 

  10. Lamia, K. A., Storch, K. F. & Weitz, C. J. Physiological significance of a peripheral tissue circadian clock. Proc. Natl Acad. Sci. USA 105, 15172–15177 (2008)

    Article  CAS  ADS  Google Scholar 

  11. Marcheva, B. et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466, 627–631 (2010)

    Article  CAS  ADS  Google Scholar 

  12. Sadacca, L. A., Lamia, K. A., deLemos, A. S., Blum, B. & Weitz, C. J. An intrinsic circadian clock of the pancreas is required for normal insulin release and glucose homeostasis in mice. Diabetologia 54, 120–124 (2010)

    Article  Google Scholar 

  13. Storch, K. F. et al. Extensive and divergent circadian gene expression in liver and heart. Nature 417, 78–83 (2002)

    Article  CAS  ADS  Google Scholar 

  14. Panda, S. et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320 (2002)

    Article  CAS  Google Scholar 

  15. Kornmann, B., Schaad, O., Bujard, H., Takahashi, J. S. & Schibler, U. System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biol. 5, e34 (2007)

    Article  Google Scholar 

  16. Schmutz, I., Ripperger, J. A., Baeriswyl-Aebischer, S. & Albrecht, U. The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors. Genes Dev. 24, 345–357 (2010)

    Article  CAS  Google Scholar 

  17. Sato, T. K. et al. A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 43, 527–537 (2004)

    Article  CAS  Google Scholar 

  18. Balsalobre, A. et al. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289, 2344–2347 (2000)

    Article  CAS  ADS  Google Scholar 

  19. Reichardt, H. M. et al. DNA binding of the glucocorticoid receptor is not essential for survival. Cell 93, 531–541 (1998)

    Article  CAS  Google Scholar 

  20. Vollmers, C. et al. Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proc. Natl Acad. Sci. USA 106, 21453–21458 (2009)

    Article  CAS  ADS  Google Scholar 

  21. Zhang, E. E. et al. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nature Med. 16, 1152–1156 (2010)

    Article  CAS  Google Scholar 

  22. So, A. Y.-L., Bernal, T. U., Pillsbury, M. L., Yamamoto, K. R. & Feldman, B. J. Glucocorticoid regulation of the circadian clock modulates glucose homeostasis. Proc. Natl Acad. Sci. USA 106, 17582–17587 (2009)

    Article  CAS  ADS  Google Scholar 

  23. Doi, M. et al. Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6. Nature Med. 16, 67–74 (2010)

    Article  CAS  Google Scholar 

  24. Barish, G. D. et al. A nuclear receptor atlas: macrophage activation. Mol. Endocrinol. 19, 2466–2477 (2005)

    Article  CAS  Google Scholar 

  25. Lamia, K. A. et al. Increased insulin sensitivity and reduced adiposity in phosphatidylinositol 5-phosphate 4-kinase β mice. Mol. Cell. Biol. 24, 5080–5087 (2004)

    Article  CAS  Google Scholar 

  26. Lavery, D. J. & Schibler, U. Circadian transcription of the cholesterol 7 alpha hydroxylase gene may involve the liver-enriched bZIP protein DBP. Genes Dev. 7, 1871–1884 (1993)

    Article  CAS  Google Scholar 

  27. Nelson, J. D., Denisenko, O. & Bomsztyk, K. Protocol for the fast chromatin immunoprecipitation (ChIP) method. Nature Protocols 1, 179–185 (2006)

    Article  CAS  Google Scholar 

  28. Stratmann, M., Stadler, F., Tamanini, F., van der Horst, G. T. & Ripperger, J. A. Flexible phase adjustment of circadian albumin D site-binding protein (DBP) gene expression by CRYPTOCHROME1. Genes Dev. 24, 1317–1328 (2010)

    Article  CAS  Google Scholar 

  29. Thresher, R. J. et al. Role of mouse cryptochrome blue-light photoreceptor in circadian photoresponses. Science 282, 1490–1494 (1998)

    Article  CAS  Google Scholar 

Download references

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

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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.

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Correspondence to Katja 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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