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Plasticity and specificity of the circadian epigenome

Nature Neuroscience volume 13, pages 1324–1329 (2010)Cite this article

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Abstract

Circadian clocks control a variety of neuronal, behavioral and physiological responses, via transcriptional regulation of an appreciable portion of the genome. We describe the complex communication network between the brain-specific central clock and the tissue-specific peripheral clocks that serve to synchronize the organism to both external and internal demands. In addition, we discuss and speculate on how epigenetic processes are involved in creating transcriptional environments that are permissive to tissue-specific gene expression programs, which work in concert with the circadian machinery. Accumulating data show that chromatin remodeling events may be critical for providing specificity and plasticity in circadian regulation, and metabolic cues may be involved in directing such epigenetic events. A detailed understanding of the communication cues between the central and peripheral clocks is crucial for a more complete understanding of the circadian system and the several levels of control that are implicated in maintaining biological timekeeping.

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Figure 1: The circadian CLOCK network.
Figure 2: What underlies the different genomic responses of central versus peripheral clocks? Approximately 10% of transcripts in a given tissue show circadian expression.
Figure 3: Chromatin remodeling and the circadian clock.

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References

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

    Article  CAS  Google Scholar 

  2. Welsh, D.K., Takahashi, J.S. & Kay, S.A. Suprachiasmatic nucleus: cell autonomy and network properties. Annu. Rev. Physiol. 72, 551–577 (2010).

    Article  CAS  Google Scholar 

  3. Bechtold, D.A., Gibbs, J.E. & Loudon, A.S. Circadian dysfunction in disease. Trends Pharmacol. Sci. 31, 191–198 (2010).

    Article  CAS  Google Scholar 

  4. Sahar, S. & Sassone-Corsi, P. Metabolism and cancer: the circadian clock connection. Nat. Rev. Cancer 9, 886–896 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Eckel-Mahan, K. & Sassone-Corsi, P. Metabolism control by the circadian clock and vice versa. Nat. Struct. Mol. Biol. 16, 462–467 (2009).

    Article  CAS  Google Scholar 

  7. Gallego, M. & Virshup, D.M. Post-translational modifications regulate the ticking of the circadian clock. Nat. Rev. Mol. Cell Biol. 8, 139–148 (2007).

    Article  CAS  Google Scholar 

  8. Aton, S.J., Colwell, C.S., Harmar, A.J., Waschek, J. & Herzog, E.D. Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat. Neurosci. 8, 476–483 (2005).

    Article  CAS  Google Scholar 

  9. Kalsbeek, A., Fliers, E., Hofman, M.A., Swaab, D.F. & Buijs, R.M. Vasopressin and the output of the hypothalamic biological clock. J. Neuroendocrinol. 22, 362–372 (2010).

    Article  CAS  Google Scholar 

  10. Tousson, E. & Meissl, H. Suprachiasmatic nuclei grafts restore the circadian rhythm in the paraventricular nucleus of the hypothalamus. J. Neurosci. 24, 2983–2988 (2004).

    Article  CAS  Google Scholar 

  11. Ralph, M.R., Foster, R.G., Davis, F.C. & Menaker, M. Transplanted suprachiasmatic nucleus determines circadian period. Science 247, 975–978 (1990).

    Article  CAS  Google Scholar 

  12. Akhtar, R.A. et al. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr. Biol. 12, 540–550 (2002).

    Article  CAS  Google Scholar 

  13. Cheng, M.Y. et al. Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 417, 405–410 (2002).

    Article  CAS  Google Scholar 

  14. Kramer, A. et al. Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 294, 2511–2515 (2001).

    Article  CAS  Google Scholar 

  15. Abe, K., Kroning, J., Greer, M.A. & Critchlow, V. Effects of destruction of the suprachiasmatic nuclei on the circadian rhythms in plasma corticosterone, body temperature, feeding and plasma thyrotropin. Neuroendocrinology 29, 119–131 (1979).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Welsh, D.K., Logothetis, D.E., Meister, M. & Reppert, S.M. Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron 14, 697–706 (1995).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. 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 

  20. Yan, J., Wang, H., Liu, Y. & Shao, C. Analysis of gene regulatory networks in the mammalian circadian rhythm. PLOS Comput. Biol. 4, e1000193 (2008).

    Article  Google Scholar 

  21. Baggs, J.E. et al. Network features of the mammalian circadian clock. PLoS Biol. 7, e52 (2009).

    Article  Google Scholar 

  22. Ueda, H.R. et al. System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat. Genet. 37, 187–192 (2005).

    Article  CAS  Google Scholar 

  23. Travnickova-Bendova, Z., Cermakian, N., Reppert, S.M. & Sassone-Corsi, P. Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity. Proc. Natl. Acad. Sci. USA 99, 7728–7733 (2002).

    Article  CAS  Google Scholar 

  24. Nader, N., Chrousos, G.P. & Kino, T. Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications. FASEB J. 23, 1572–1583 (2009).

    Article  CAS  Google Scholar 

  25. Duffield, G.E. et al. A role for Id2 in regulating photic entrainment of the mammalian circadian system. Curr. Biol. 19, 297–304 (2009).

    Article  CAS  Google Scholar 

  26. 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 

  27. Duffield, G.E. et al. Circadian programs of transcriptional activation, signaling, and protein turnover revealed by microarray analysis of mammalian cells. Curr. Biol. 12, 551–557 (2002).

    Article  CAS  Google Scholar 

  28. Crosio, C., Cermakian, N., Allis, C.D. & Sassone-Corsi, P. Light induces chromatin modification in cells of the mammalian circadian clock. Nat. Neurosci. 3, 1241–1247 (2000).

    Article  CAS  Google Scholar 

  29. Etchegaray, J.P., Lee, C., Wade, P.A. & Reppert, S.M. Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421, 177–182 (2003).

    Article  CAS  Google Scholar 

  30. Nakahata, Y. et al. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134, 329–340 (2008).

    Article  CAS  Google Scholar 

  31. Cheung, P. et al. Synergistic coupling of histone H3 phosphorylation and acetylation in response to epidermal growth factor stimulation. Mol. Cell 5, 905–915 (2000).

    Article  CAS  Google Scholar 

  32. Tu, H. et al. Dominant role of GABAB2 and Gβγ for GABAB receptor-mediated-ERK1/2/CREB pathway in cerebellar neurons. Cell. Signal. 19, 1996–2002 (2007).

    Article  CAS  Google Scholar 

  33. Ding, J.M. et al. Resetting the biological clock: mediation of nocturnal circadian shifts by glutamate and NO. Science 266, 1713–1717 (1994).

    Article  CAS  Google Scholar 

  34. Impey, S. et al. Phosphorylation of CBP mediates transcriptional activation by neural activity and CaM kinase IV. Neuron 34, 235–244 (2002).

    Article  CAS  Google Scholar 

  35. Yujnovsky, I., Hirayama, J., Doi, M., Borrelli, E. & Sassone-Corsi, P. Signaling mediated by the dopamine D2 receptor potentiates circadian regulation by CLOCK:BMAL1. Proc. Natl. Acad. Sci. USA 103, 6386–6391 (2006).

    Article  CAS  Google Scholar 

  36. Doi, M., Hirayama, J. & Sassone-Corsi, P. Circadian regulator CLOCK is a histone acetyltransferase. Cell 125, 497–508 (2006).

    Article  CAS  Google Scholar 

  37. Ripperger, J.A. & Schibler, U. Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nat. Genet. 38, 369–374 (2006).

    Article  CAS  Google Scholar 

  38. Hirayama, J. et al. CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature 450, 1086–1090 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  40. Alenghat, T. et al. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 456, 997–1000 (2008).

    Article  CAS  Google Scholar 

  41. Katada, S. & Sassone-Corsi, P. The histone methyltransferase MLL1 permits the oscillation of circadian gene expression. Nat. Struct. Mol. Biol. (in the press).

  42. Etchegaray, J.P. et al. The polycomb group protein EZH2 is required for mammalian circadian clock function. J. Biol. Chem. 281, 21209–21215 (2006).

    Article  CAS  Google Scholar 

  43. Roozendaal, B. et al. Membrane-associated glucocorticoid activity is necessary for modulation of long-term memory via chromatin modification. J. Neurosci. 30, 5037–5046 (2010).

    Article  CAS  Google Scholar 

  44. Chwang, W.B., Arthur, J.S., Schumacher, A. & Sweatt, J.D. The nuclear kinase mitogen- and stress-activated protein kinase 1 regulates hippocampal chromatin remodeling in memory formation. J. Neurosci. 27, 12732–12742 (2007).

    Article  CAS  Google Scholar 

  45. Gao, J. et al. A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 466, 1105–1109 (2010).

    Article  CAS  Google Scholar 

  46. Nakahata, Y., Sahar, S., Astarita, G., Kaluzova, M. & Sassone-Corsi, P. Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science 324, 654–657 (2009).

    Article  CAS  Google Scholar 

  47. Ramsey, K.M. et al. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324, 651–654 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  49. Womac, A.D., Burkeen, J.F., Neuendorff, N., Earnest, D.J. & Zoran, M.J. Circadian rhythms of extracellular ATP accumulation in suprachiasmatic nucleus cells and cultured astrocytes. Eur. J. Neurosci. 30, 869–876 (2009).

    Article  Google Scholar 

  50. Belden, W.J., Loros, J.J. & Dunlap, J.C. Execution of the circadian negative feedback loop in Neurospora requires the ATP-dependent chromatin-remodeling enzyme CLOCKSWITCH. Mol. Cell 25, 587–600 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all members of our laboratory for discussions and support. Work in the laboratory is supported by the US National Institute of Health and the INSERM (Institut National de la Santé et la Recherche Médicale), France.

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  1. Department of Pharmacology, U904 INSERM 'Epigenetics and Neuronal Plasticity', School of Medicine, University of California, Irvine, California, USA

    Selma Masri & Paolo Sassone-Corsi

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Correspondence to Paolo Sassone-Corsi.

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Masri, S., Sassone-Corsi, P. Plasticity and specificity of the circadian epigenome. Nat Neurosci 13, 1324–1329 (2010). https://doi.org/10.1038/nn.2668

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