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Circadian rhythms persist without transcription in a eukaryote

Abstract

Circadian rhythms are ubiquitous in eukaryotes, and coordinate numerous aspects of behaviour, physiology and metabolism, from sleep/wake cycles in mammals to growth and photosynthesis in plants1,2. This daily timekeeping is thought to be driven by transcriptional–translational feedback loops, whereby rhythmic expression of ‘clock’ gene products regulates the expression of associated genes in approximately 24-hour cycles. The specific transcriptional components differ between phylogenetic kingdoms3. The unicellular pico-eukaryotic alga Ostreococcus tauri possesses a naturally minimized clock, which includes many features that are shared with plants, such as a central negative feedback loop that involves the morning-expressed CCA1 and evening-expressed TOC1 genes4. Given that recent observations in animals and plants have revealed prominent post-translational contributions to timekeeping5, a reappraisal of the transcriptional contribution to oscillator function is overdue. Here we show that non-transcriptional mechanisms are sufficient to sustain circadian timekeeping in the eukaryotic lineage, although they normally function in conjunction with transcriptional components. We identify oxidation of peroxiredoxin proteins as a transcription-independent rhythmic biomarker, which is also rhythmic in mammals6. Moreover we show that pharmacological modulators of the mammalian clock mechanism have the same effects on rhythms in Ostreococcus. Post-translational mechanisms, and at least one rhythmic marker, seem to be better conserved than transcriptional clock regulators. It is plausible that the oldest oscillator components are non-transcriptional in nature, as in cyanobacteria7, and are conserved across kingdoms.

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Figure 1: Transcriptionally inactive cells show a phase-dependent response to re-illumination.
Figure 2: Circadian cycles of PRX oxidation are detected during light/dark cycles and in constant darkness, and persist during drug inhibition of gene expression.
Figure 3: Circadian timing can survive the inhibition of cellular transcription, or cytosolic translation.
Figure 4: Circadian period in O. tauri can be modulated pharmacologically in a dose-dependent manner by the application of inhibitors that have been previously validated in other taxa.

References

  1. Harmer, S. L. The circadian system in higher plants. Annu. Rev. Plant Biol. 60, 357–377 (2009)

    Article  CAS  Google Scholar 

  2. Reddy, A. B. & O’Neill, J. S. Healthy clocks, healthy body, healthy mind. Trends Cell. Biol. 20, 36–44 (2010)

    Article  Google Scholar 

  3. Lakin-Thomas, P. L. Transcriptional feedback oscillators: maybe, maybe not. J. Biol. Rhythms 21, 83–92 (2006)

    Article  CAS  Google Scholar 

  4. Corellou, F. et al. Clocks in the green lineage: Comparative functional analysis of the circadian architecture of the picoeukaryote Ostreococcus . Plant Cell 21, 3436–3449 (2009)

    Article  CAS  Google Scholar 

  5. Hastings, M. H., Maywood, E. S. & O’Neill, J. S. Cellular circadian pacemaking and the role of cytosolic rhythms. Curr. Biol. 18, R805–R815 (2008)

    Article  CAS  Google Scholar 

  6. Reddy, A. B. et al. Circadian orchestration of the hepatic proteome. Curr. Biol. 16, 1107–1115 (2006)

    Article  CAS  Google Scholar 

  7. Nakajima, M. et al. Reconstitution of circadian oscillation of cyanobacterial KaiC phosphorylation in vitro . Science 308, 414–415 (2005)

    Article  ADS  CAS  Google Scholar 

  8. Roenneberg, T. & Merrow, M. Circadian clocks—the fall and rise of physiology. Nature Rev. Mol. Cell Biol. 6, 965–971 (2005)

    Article  CAS  Google Scholar 

  9. Ueda, H. R. Systems biology flowering in the plant clock field. Mol. Syst. Biol. 2, 60 (2006)

    Article  Google Scholar 

  10. Mehra, A., Baker, C. L., Loros, J. J. & Dunlap, J. C. Post-translational modifications in circadian rhythms. Trends Biochem. Sci. 34, 483–490 (2009)

    Article  CAS  Google Scholar 

  11. Merrow, M., Mazzotta, G., Chen, Z. & Roenneberg, T. The right place at the right time: regulation of daily timing by phosphorylation. Genes Dev. 20, 2629–2633 (2006)

    Article  CAS  Google Scholar 

  12. O’Neill, J. S., Maywood, E. S., Chesham, J. E., Takahashi, J. S. & Hastings, M. H. cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science 320, 949–953 (2008)

    Article  ADS  Google Scholar 

  13. Woolum, J. C. A re-examination of the role of the nucleus in generating the circadian rhythm in Acetabularia. J. Biol. Rhythms 6, 129–136 (1991)

    Article  CAS  Google Scholar 

  14. Morse, D. S., Fritz, L. & Hastings, J. W. What is the clock? Translational regulation of circadian bioluminescence. Trends Biochem. Sci. 15, 262–265 (1990)

    Article  CAS  Google Scholar 

  15. Monnier, A. et al. Orchestrated transcription of biological processes in the marine picoeukaryote Ostreococcus exposed to light/dark cycles. BMC Genomics 11, 192 (2010)

    Article  Google Scholar 

  16. Moulager, M. et al. Light-dependent regulation of cell division in Ostreococcus: evidence for a major transcriptional input. Plant Physiol. 144, 1360–1369 (2007)

    Article  CAS  Google Scholar 

  17. Konopka, R. J. Genetic dissection of the Drosophila circadian system. Fed. Proc. 38, 2602–2605 (1979)

    CAS  PubMed  Google Scholar 

  18. Hall, A., Karplus, P. A. & Poole, L. B. Typical 2-Cys peroxiredoxins–structures, mechanisms and functions. FEBS J. 276, 2469–2477 (2009)

    Article  CAS  Google Scholar 

  19. Baier, M. & Dietz, K. J. The plant 2-Cys peroxiredoxin BAS1 is a nuclear-encoded chloroplast protein: its expressional regulation, phylogenetic origin, and implications for its specific physiological function in plants. Plant J. 12, 179–190 (1997)

    Article  CAS  Google Scholar 

  20. O’Neill, J. S. & Reddy, A. B. Circadian clocks in human red blood cells. Nature doi:10.1038/nature09702 (this issue).

  21. Khalsa, S. B., Whitmore, D., Bogart, B. & Block, G. D. Evidence for a central role of transcription in the timing mechanism of a circadian clock. Am. J. Physiol. 271, C1646–C1651 (1996)

    Article  CAS  Google Scholar 

  22. Edwards, K. D. et al. FLOWERING LOCUS C mediates natural variation in the high-temperature response of the Arabidopsis circadian clock. Plant Cell 18, 639–650 (2006)

    Article  CAS  Google Scholar 

  23. McClung, C. R. Plant circadian rhythms. Plant Cell 18, 792–803 (2006)

    Article  CAS  Google Scholar 

  24. Dodd, A. N. et al. The Arabidopsis circadian clock incorporates a cADPR-based feedback loop. Science 318, 1789–1792 (2007)

    Article  ADS  CAS  Google Scholar 

  25. Eide, E. J. et al. Control of mammalian circadian rhythm by CKIε-regulated proteasome-mediated PER2 degradation. Mol. Cell. Biol. 25, 2795–2807 (2005)

    Article  CAS  Google Scholar 

  26. Hirota, T. et al. A chemical biology approach reveals period shortening of the mammalian circadian clock by specific inhibition of GSK-3β. Proc. Natl Acad. Sci. USA 105, 20746–20751 (2008)

    Article  ADS  CAS  Google Scholar 

  27. Isojima, Y. et al. CKIε/δ-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock. Proc. Natl Acad. Sci. USA 106, 15744–15749 (2009)

    Article  ADS  CAS  Google Scholar 

  28. Johnson, C. H., Mori, T. & Xu, Y. A cyanobacterial circadian clockwork. Curr. Biol. 18, R816–R825 (2008)

    Article  CAS  Google Scholar 

  29. Eelderink-Chen, Z. et al. A circadian clock in Saccharomyces cerevisiae . Proc. Natl Acad. Sci. USA 107, 2043–2047 (2010)

    Article  ADS  CAS  Google Scholar 

  30. Edwards, K. D. et al. Quantitative analysis of regulatory flexibility under changing environmental conditions. Mol. Syst. Biol. 6, 424 (2010)

    Article  Google Scholar 

Download references

Acknowledgements

CSBE is a Centre for Integrative Systems Biology funded by BBSRC and EPSRC award D019621. C.T. is supported by a BBSRC/ANR joint project F005466 awarded to F.-Y.B. and A.J.M. and by the HFSP. A.B.R. is supported by the Wellcome Trust (083643/Z/07/Z) and the MRC Centre for Obesity and Related metabolic Disorders (MRC CORD).

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J.S.O’N., G.v.O. and L.E.D. designed and performed the experiments; J.S.O’N., G.v.O., L.E.D., C.T., A.B.R. and A.J.M. analysed data. F.-Y.B. and F.C. generated essential protocols and biomaterials. All authors contributed to writing. J.S.O’N. and G.v.O. contributed equally to this paper.

Corresponding authors

Correspondence to Akhilesh B. Reddy or Andrew J. Millar.

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The authors declare no competing financial interests.

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O’Neill, J., van Ooijen, G., Dixon, L. et al. Circadian rhythms persist without transcription in a eukaryote. Nature 469, 554–558 (2011). https://doi.org/10.1038/nature09654

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