Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Extensive and divergent circadian gene expression in liver and heart

A Corrigendum to this article was published on 08 August 2002

Abstract

Many mammalian peripheral tissues have circadian clocks1,2,3,4; endogenous oscillators that generate transcriptional rhythms thought to be important for the daily timing of physiological processes5,6. The extent of circadian gene regulation in peripheral tissues is unclear, and to what degree circadian regulation in different tissues involves common or specialized pathways is unknown. Here we report a comparative analysis of circadian gene expression in vivo in mouse liver and heart using oligonucleotide arrays representing 12,488 genes. We find that peripheral circadian gene regulation is extensive (≥8–10% of the genes expressed in each tissue), that the distributions of circadian phases in the two tissues are markedly different, and that very few genes show circadian regulation in both tissues. This specificity of circadian regulation cannot be accounted for by tissue-specific gene expression. Despite this divergence, the clock-regulated genes in liver and heart participate in overlapping, extremely diverse processes. A core set of 37 genes with similar circadian regulation in both tissues includes candidates for new clock genes and output genes, and it contains genes responsive to circulating factors with circadian or diurnal rhythms.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Temporal profiles of circadian gene expression in liver (a, b) and heart (c, d).
Figure 2: Global comparison of biological processes associated with the genes exhibiting circadian expression in liver and heart.
Figure 3: Temporal expression profiles of genes showing circadian regulation in both liver and heart.
Figure 4: Individual circadian expression profiles of selected genes from the set common to liver and heart.

References

  1. Balsalobre, A., Damiola, F. & Schibler, U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93, 929–937 (1998)

    CAS  Article  Google Scholar 

  2. Yamazaki, S. et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science 288, 682–685 (2000)

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  4. McNamara, P. et al. Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock. Cell 105, 877–889 (2001)

    CAS  Article  Google Scholar 

  5. Reppert, S. M. & Weaver, D. R. Molecular analysis of mammalian circadian rhythms. Annu. Rev. Physiol. 63, 647–676 (2001)

    CAS  Article  Google Scholar 

  6. Ripperger, J. A. & Schibler, U. Circadian regulation of gene expression in animals. Curr. Opin. Cell Biol. 13, 357–362 (2001)

    CAS  Article  Google Scholar 

  7. Lockhart, D. J. et al. Expression monitoring by hybridization to high-density oligonucleotide arrays. Nature Biotechnol. 14, 1675–1680 (1996)

    CAS  Article  Google Scholar 

  8. Li, C. & Wong, W. H. Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc. Natl Acad. Sci. USA 98, 31–36 (2001)

    ADS  CAS  Article  Google Scholar 

  9. Claverie, J.-M. Gene number: what if there are only 30,000 human genes? Science 291, 1255–1257 (2001)

    CAS  Article  Google Scholar 

  10. Murphy, W. J., Stanyon, R. & O'Brien, S. J. Evolution of mammalian genome organization inferred from comparative gene mapping. Genome Biol. (Review) 2, 0005.1–0005.8 (2001)

    Google Scholar 

  11. Kornmann, B., Preitner, N., Rifat, D., Fleury-Olela, F. & Schibler, U. Analysis of circadian liver gene expression by ADDER, a highly sensitive method for the display of differentially expressed mRNAs. Nucleic Acids Res. 29, E51 (2001)

    CAS  Article  Google Scholar 

  12. Velculescu, V. E. et al. Analysis of human transcriptomes. Nature Genet. 23, 387–388 (1999)

    CAS  Article  Google Scholar 

  13. Klein, D. C., Moore, R. Y. & Reppert, S. M. (eds) Suprachiasmatic Nucleus: The Mind's Clock (Oxford Univ. Press, New York, 1991)

    Google Scholar 

  14. Grundschober, C. et al. Circadian regulation of diverse gene products revealed by mRNA expression profiling of synchronized fibroblasts. J. Biol. Chem. 276, 46751–46758 (2001)

    CAS  Article  Google Scholar 

  15. Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nature Genet. 25, 25–29 (2000)

    CAS  Article  Google Scholar 

  16. Torra, I. P. et al. Circadian and glucocorticoid regulation of Rev-erb-alpha expression in liver. Endocrinology 141, 3799–3806 (2000)

    CAS  Article  Google Scholar 

  17. Ripperger, J. A., Shearman, L. P., Reppert, S. M. & Schibler, U. CLOCK, an essential pacemaker component, controls expression of the circadian transcription factor DBP. Genes Dev. 14, 679–689 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Young, M. W. & Kay, S. A. Time zones: a comparative genetics of circadian clocks. Nature Rev. Genet. 2, 702–715 (2001)

    CAS  Article  Google Scholar 

  19. Tata, J. R., Baker, B. S., Machuca, I., Rabelo, E. M. & Yamauchi, K. Autoinduction of nuclear receptor genes and its significance. J. Steroid Biochem. Mol. Biol. 46, 105–119 (1993)

    CAS  Article  Google Scholar 

  20. Kalsbeek, A., Fliers, E., Franke, A. N., Worte, J. & Buijs, R. M. Functional connections between the suprachiasmatic nucleus and the thyroid gland as revealed by lesioning and viral tracing techniques in the rat. Endocrinology 141, 3832–3841 (2000)

    CAS  Article  Google Scholar 

  21. Harris, H. J., Kotelevtsev, Y., Mullins, J. J., Seckl, J. R. & Holmes, M. C. Intracellular regeneration of glucocorticoids by 11beta-hydroxysteroid dehydrogenase (11beta-HSD)-1 plays a key role in regulation of the hypothalamic-pituitary-adrenal axis: analysis of 11beta-HSD-1-deficient mice. Endocrinology 142, 114–120 (2001)

    CAS  Article  Google Scholar 

  22. Chen, J., Maltby, K. M. & Miano, J. M. A novel retinoid-response gene set in vascular smooth muscle cells. Biochem. Biophys. Res. Commun. 281, 475–482 (2001)

    CAS  Article  Google Scholar 

  23. Wolf, F. W. et al. B94, a primary response gene inducible by tumour necrosis factor-alpha, is expressed in developing hematopoietic tissues and the sperm acrosome. J. Biol. Chem. 269, 3633–3640 (1994)

    CAS  PubMed  Google Scholar 

  24. Cooper, P., Potter, S., Mueck, B., Yousefi, S. & Jarai, G. Identification of genes induced by inflammatory cytokines in airway epithelium. Am. J. Physiol. Lung Cell. Mol. Physiol. 280, L841–L852 (2001)

    CAS  Article  Google Scholar 

  25. Buchan, P. et al. Repeated topical administration of all-trans-retinoic acid and plasma levels of retinoic acids in humans. J. Am. Acad. Dermatol. 30, 428–434 (1994)

    CAS  Article  Google Scholar 

  26. Petrovsky, N. & Harrison, L. C. The chronobiology of human cytokine production. Int. Rev. Immunol. 16, 635–649 (1998)

    CAS  Article  Google Scholar 

  27. Harmer, S. L. et al. Orchestrated transcription of key pathways in Arabidopsis by the circadian clock. Science 290, 2110–2113 (2000)

    ADS  CAS  Article  Google Scholar 

  28. Claridge-Chang, A. et al. Circadian regulation of gene expression systems in the Drosophila head. Neuron 32, 657–671 (2001)

    CAS  Article  Google Scholar 

  29. McDonald, M. J. & Rosbash, M. Microarray analysis and organization of circadian gene expression in Drosophila. Cell 107, 567–578 (2001)

    CAS  Article  Google Scholar 

  30. Panda, S. J. et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell [online 2 April 2001] 10.1016/S0092867402007225 (2002)

Download references

Acknowledgements

This work was supported by the Edward R. and Anne G. Lefler Center, Harvard Medical School and the National Eye Institute (C.J.W.), a Deutsche Forschungsgemeinschaft Postdoctoral Fellowship (K-F.S.), the National Institute of Child Health and Human Development (F.C.D. and N.V.), and the National Human Genome Research Institute (W.H.W.). We thank S. Meng and the Harvard Center for Genomics Research for technical assistance and M.-C. Kao for programming.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Charles J. Weitz.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Storch, KF., Lipan, O., Leykin, I. et al. Extensive and divergent circadian gene expression in liver and heart. Nature 417, 78–83 (2002). https://doi.org/10.1038/nature744

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature744

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing