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Review article: Biomedical intelligence

Vol. 144 No. 2930 (2014)

Circadian rhythms – from genes to physiology and disease

  • Thomas Bollinger
  • Ueli Schibler
DOI
https://doi.org/10.4414/smw.2014.13984
Cite this as:
Swiss Med Wkly. 2014;144:w13984
Published
14.07.2014

Summary

Most physiological processes in our body oscillate in a daily fashion. These include cerebral activity (sleep-wake cycles), metabolism and energy homeostasis, heart rate, blood pressure, body temperature, renal activity, and hormone as well as cytokine secretion. The daily rhythms in behaviour and physiology are not just acute responses to timing cues provided by the environment, but are driven by an endogenous circadian timing system. A central pacemaker in the suprachiasmatic nucleus (SCN), located in the ventral hypothalamus, coordinates all overt rhythms in our body through neuronal and humoral outputs. The SCN consists of two tiny clusters of ~100,000 neurones in humans, each harbouring a self-sustained, cell-autonomous molecular oscillator. Research conducted during the past years has shown, however, that virtually all of our thirty-five trillion body cells possess their own clocks and that these are indistinguishable from those operative in SCN neurones. Here we give an overview on the molecular and cellular architecture of the mammalian circadian timing system and provide some thoughts on its medical and social impact.

References

  1. Dibner C, Schibler U, Albrecht U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu Rev Physiol. 2010;72:517–49.
  2. Partch CL, Green CB, Takahashi JS. Molecular architecture of the mammalian circadian clock. Trends Cell Biol. 2014;24(2):90–9.
  3. Ralph MR, Foster RG, Davis FC, Menaker M. Transplanted suprachiasmatic nucleus determines circadian period. Science. 1990;247(4945):975–8.
  4. Tosini G, Menaker M. Circadian rhythms in cultured mammalian retina. Science. 1996;272(5260):419–21.
  5. Balsalobre A, Damiola F, Schibler U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell. 1998;93(6):929–37.
  6. Yamazaki S, Numano R, Abe M, Hida A, Takahashi R, Ueda M, et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science. 2000;288(5466):682–5.
  7. Bianconi E, Piovesan A, Facchin F, Beraudi A, Casadei R, Frabetti F, et al. An estimation of the number of cells in the human body. Ann Hum Biol. 2013;40(6):463–71.
  8. Nagoshi E, Saini C, Bauer C, Laroche T, Naef F, Schibler U. Circadian gene expression in individual fibroblasts: cell-autonomous and self-sustained oscillators pass time to daughter cells. Cell. 2004;119(5):693–705.
  9. Welsh DK, Yoo SH, Liu AC, Takahashi JS, Kay SA. Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression. Curr Biol. 2004;14(24):2289–95.
  10. Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci. 1995;15(5 Pt 1):3526–38.
  11. Richards J, Gumz ML. Mechanism of the circadian clock in physiology. Am J Physiol Regul Integr Comp Physiol. 2013;304(12):R1053–64.
  12. Morris CJ, Yang JN, Scheer FA. The impact of the circadian timing system on cardiovascular and metabolic function. Prog Brain Res. 2012;199:337–58.
  13. Firsov D, Tokonami N, Bonny O. Role of the renal circadian timing system in maintaining water and electrolytes homeostasis. Mol Cell Endocrinol. 2012;349(1):51–5.
  14. Tsang AH, Barclay JL, Oster H. Interactions between endocrine and circadian systems. J Mol Endocrinol. 2014;52(1):R1–16.
  15. Asher G, Schibler U. Crosstalk between components of circadian and metabolic cycles in mammals. Cell Metab. 2011;13(2):125–37.
  16. Scheiermann C, Kunisaki Y, Frenette PS. Circadian control of the immune system. Nat Rev Immunol. 2013;13(3):190–8.
  17. Refinetti R. The circadian rhythm of body temperature. Front Biosci (Landmark Ed). 2010;15:564–94.
  18. Buhr ED, Takahashi JS. Molecular components of the Mammalian circadian clock. Handb Exp Pharmacol. 2013(217):3–27.
  19. Feng D, Liu T, Sun Z, Bugge A, Mullican SE, Alenghat T, et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science. 2011;331(6022):1315–9.
  20. Reischl S, Kramer A. Kinases and phosphatases in the mammalian circadian clock. FEBS Lett. 2011;585(10):1393–9.
  21. O’Neill JS, Reddy AB. The essential role of cAMP/Ca2+ signalling in mammalian circadian timekeeping. Biochem Soc Trans. 2012;40(1):44–50.
  22. Harmar AJ. An essential role for peptidergic signalling in the control of circadian rhythms in the suprachiasmatic nuclei. J Neuroendocrinol. 2003;15(4):335–8.
  23. Richardson GS, Moore-Ede MC, Czeisler CA, Dement WC. Circadian rhythms of sleep and wakefulness in mice: analysis using long-term automated recording of sleep. Am J Physiol. 1985;248(3 Pt 2):R320–30.
  24. Schmidt TM, Chen SK, Hattar S. Intrinsically photosensitive retinal ganglion cells: many subtypes, diverse functions. Trends Neurosci. 2011;34(11):572–80.
  25. Chen SK, Badea TC, Hattar S. Photoentrainment and pupillary light reflex are mediated by distinct populations of ipRGCs. Nature. 2011;476(7358):92–5.
  26. Khalsa SB, Jewett ME, Cajochen C, Czeisler CA. A phase response curve to single bright light pulses in human subjects. J Physiol. 2003;549(Pt 3):945–52.
  27. Ruger M, et al. Human phase response curve to a single 6.5 h pulse of short-wavelength light. J Physiol. 2013;591(Pt 1):353–63.
  28. Sujino M, St Hilaire MA, Brainard GC, Khalsa SB, Kronauer RE, Czeisler CA, et al. Suprachiasmatic nucleus grafts restore circadian behavioral rhythms of genetically arrhythmic mice. Curr Biol. 2003;13(8):664–8.
  29. Silver R, LeSauter J, Tresco PA, Lehman MN. A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms. Nature. 1996;382(6594):810–3.
  30. Li JD, Hu WP, Zhou QY. The circadian output signals from the suprachiasmatic nuclei. Prog Brain Res. 2012;199:119–27.
  31. Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F, Schibler U. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 2000;14(23):2950–2961.
  32. Stokkan KA, Yamazaki S, Tei H, Sakaki Y, Menaker M. Entrainment of the circadian clock in the liver by feeding. Science. 2001;291(5503):490–3.
  33. Kornmann B, Schaad O, Bujard H, Takahashi JS, Schibler U. System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biol. 2007;5(2): p. e34.
  34. Brown SA, Zumbrunn G, Fleury-Olela F, Preitner N, Schibler U. Rhythms of mammalian body temperature can sustain peripheral circadian clocks. Curr Biol. 2002;12(18):1574–83.
  35. Buhr ED, Yoo SH, Takahashi JS. Temperature as a universal resetting cue for mammalian circadian oscillators. Science. 2010;330(6002):379–85.
  36. Morf J, Rey G, Schneider K, Stratmann M, Fujita J, Naef F, et al. Cold-inducible RNA-binding protein modulates circadian gene expression posttranscriptionally. Science. 2012;338(6105):379–83.
  37. Saini C, Morf J, Stratmann M, Gos P, Schibler U. Simulated body temperature rhythms reveal the phase-shifting behavior and plasticity of mammalian circadian oscillators. Genes Dev. 2012;26(6):567–80.
  38. Le Minh N, Damiola F, Tronche F, Schütz G, Schibler U. Glucocorticoid hormones inhibit food-induced phase-shifting of peripheral circadian oscillators. Embo J. 2001;20(24):7128–7136.
  39. Reddy AB, Maywood ES, Karp NA, King VM, Inoue Y, et al. Glucocorticoid signaling synchronizes the liver circadian transcriptome. Hepatology. 2007;45(6):1478–88.
  40. Gerber A, Esnault C, Aubert G, Treisman R, Pralong F, Schibler U. Blood-Borne Circadian Signal Stimulates Daily Oscillations in Actin Dynamics and SRF Activity. Cell. 2013;152(3):492–503.
  41. Aschoff J, Wever R. Human circadian rhythms: a multioscillatory system. Fed Proc. 1976;35(12):236–32.
  42. Daan S, Beersma DG, Borbely AA. Timing of human sleep: recovery process gated by a circadian pacemaker. Am J Physiol. 1984;246(2 Pt 2):R161–83.
  43. Mirmiran M, Lunshof S. Perinatal development of human circadian rhythms. Prog Brain Res. 1996;111:217–26.
  44. Mirmiran M, Ariagno RL. Influence of light in the NICU on the development of circadian rhythms in preterm infants. Semin Perinatol. 2000;24(4):247–57.
  45. Mirmiran M, Maas YG, Ariagno RL. Development of fetal and neonatal sleep and circadian rhythms. Sleep Med Rev. 2003;7(4):321–34.
  46. Hofman MA, Swaab DF. Living by the clock: the circadian pacemaker in older people. Ageing Res Rev. 2006;5(1):33–51.
  47. Zhou JN, Liu RY, van Heerikhuize J, Hofman MA, Swaab DF. Alterations in the circadian rhythm of salivary melatonin begin during middle-age. J Pineal Res. 2003;34(1):11–6.
  48. Karasek M. Melatonin, human aging, and age-related diseases. Exp Gerontol. 2004;39(11–12):1723–9.
  49. Roenneberg T, Kuehnle T, Juda M, Kantermann T, Allebrandt K, Gordijn M, et al. Epidemiology of the human circadian clock. Sleep Med Rev. 2007;11(6):429–38.
  50. Roenneberg T, Allebrandt KV, Merrow M, Vetter C. Social jetlag and obesity. Curr Biol. 2012;22(10):939–43.
  51. Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science. 2001;291(5506):1040–3.
  52. Shanware NP, Hutchinson JA, Kim SH, Zhan L, Bowler MJ, Tibbetts RS. Casein kinase 1–dependent phosphorylation of familial advanced sleep phase syndrome-associated residues controls PERIOD 2 stability. J Biol Chem. 2011;286(14):12766–74.
  53. Kurlansik SL, Ibay AD. Seasonal affective disorder. Am Fam Physician. 2012;86(11):1037–41.
  54. Levitan RD. The chronobiology and neurobiology of winter seasonal affective disorder. Dialogues Clin Neurosci. 2007;9(3):315–24.
  55. Schernhammer ES, Feskanich D, Liang G, Han J. Rotating night-shift work and lung cancer risk among female nurses in the United States. Am J Epidemiol. 2013;178(9):1434–41.
  56. Portal-Nunez S, Shankavaram UT, Rao M, Datrice N, Atay S, Aparicio M, et al. Aryl hydrocarbon receptor-induced adrenomedullin mediates cigarette smoke carcinogenicity in humans and mice. Cancer Res. 2012;72(22) 5790–800.
  57. Tanimura N, Kusunose N, Matsunaga N, Koyanagi S, Ohdo S. Aryl hydrocarbon receptor-mediated Cyp1a1 expression is modulated in a CLOCK-dependent circadian manner. Toxicology. 2011;290(2–3):203–7.
  58. Grundy A, Richardson H, Burstyn I, Lohrisch C, SenGupta SK, Lai AS, et al. Increased risk of breast cancer associated with long-term shift work in Canada. Occup Environ Med. 2013;70(12):831–8.
  59. Wang F, Yeung KL, Chan WC, Kwok CC, Leung SL, et al. A meta-analysis on dose-response relationship between night shift work and the risk of breast cancer. Ann Oncol. 2013;24(11):2724–32.
  60. Ijaz S, Verbeek J, Seidler A, Lindbohm ML, Ojajärvi A, Orsini N, et al. Night-shift work and breast cancer – a systematic review and meta-analysis. Scand J Work Environ Health. 2013;39(5):431–47.
  61. Kamdar BB, Tergas AI, Mateen FJ, Bhayani NH, Oh J. Night-shift work and risk of breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat. 2013;138(1):291–301.
  62. Filipski E, Li XM, Levi F. Disruption of circadian coordination and malignant growth. Cancer Causes Control. 2006;17(4):509–14.
  63. Li XM, Delaunay F, Dulong S, Claustrat B, Zampera S, Fujii Y, et al. Cancer inhibition through circadian reprogramming of tumor transcriptome with meal timing. Cancer Res. 2010;70(8):3351–60.
  64. Davidson AJ, Sellix MT, Daniel J, Yamazaki S, Menaker M, Block GD. Chronic jet-lag increases mortality in aged mice. Curr Biol. 2006;16(21):R914–6.
  65. Filipski E, Innominato PF, Wu M, Li XM, Iacobelli S, Xian LJ, et al. Effects of light and food schedules on liver and tumor molecular clocks in mice. J Natl Cancer Inst. 2005;97(7):507–17.
  66. Amani R, Gill T. Shiftworking, nutrition and obesity: implications for workforce health- a systematic review. Asia Pac J Clin Nutr. 2013;22(4):505–15.
  67. Knutsson A, Boggild H. Shiftwork and cardiovascular disease: review of disease mechanisms. Rev Environ Health. 2000;15(4):359–72.
  68. Dodd AN, Salathia N, Hall A, Kévei E, Tóth R, Nagy F, et al. Plant circadian clocks increase photosynthesis, growth, survival, and competitive advantage. Science. 2005;309(5734):630–3.
  69. Johnson CH, Mori T, Xu Y. A cyanobacterial circadian clockwork. Curr Biol. 2008;18(17):R816–R825.
  70. Buttgereit F, Mehta D, Kirwan J, Szechinski J, Boers M, Alten RE, et al. Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann Rheum Dis. 2013;72(2):204–10.
  71. Ortiz-Tudela E, Mteyrek A, Ballesta A, Innominato PF, Lévi F. Cancer chronotherapeutics: experimental, theoretical, and clinical aspects. Handb Exp Pharmacol. 2013;(217):261–88.
  72. Borbely AA, Achermann P. Sleep homeostasis and models of sleep regulation. J Biol Rhythms. 1999;14(6):557–68.