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.

  • Letter
  • Published:

Extensive and divergent circadian gene expression in liver and heart

Nature volume 417, pages 78–83 (2002)Cite this article

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

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)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  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

  1. Department of Neurobiology, Harvard Medical School, Northeastern University, Boston, Massachusetts, 02115, USA

    Kai-Florian Storch & Charles J. Weitz

  2. Department of Biostatistics, Harvard School of Public Health, Northeastern University, Boston, Massachusetts, 02115, USA

    Ovidiu Lipan, Igor Leykin & Wing H. Wong

  3. Department of Biology, Northeastern University, Boston, Massachusetts, 02115, USA

    N. Viswanathan & Fred C. Davis

  4. Department of Statistics, Harvard University, Cambridge, Massachusetts, 02138, USA

    Wing H. Wong

Authors
  1. Kai-Florian Storch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ovidiu Lipan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Igor Leykin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N. Viswanathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fred C. Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wing H. Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Charles J. Weitz
    View author publications

    You can also search for this author in PubMed Google Scholar

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

Advanced 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