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Molecular mechanisms and physiological importance of circadian rhythms

Abstract

To accommodate daily recurring environmental changes, animals show cyclic variations in behaviour and physiology, which include prominent behavioural states such as sleep–wake cycles but also a host of less conspicuous oscillations in neurological, metabolic, endocrine, cardiovascular and immune functions. Circadian rhythmicity is created endogenously by genetically encoded molecular clocks, whose components cooperate to generate cyclic changes in their own abundance and activity, with a periodicity of about a day. Throughout the body, such molecular clocks convey temporal control to the function of organs and tissues by regulating pertinent downstream programmes. Synchrony between the different circadian oscillators and resonance with the solar day is largely enabled by a neural pacemaker, which is directly responsive to certain environmental cues and able to transmit internal time-of-day representations to the entire body. In this Review, we discuss aspects of the circadian clock in Drosophila melanogaster and mammals, including the components of these molecular oscillators, the function and mechanisms of action of central and peripheral clocks, their synchronization and their relevance to human health.

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Fig. 1: The Drosophila melanogaster molecular clock.
Fig. 2: The expression of several circadian clock genes oscillates over the day–night cycle.
Fig. 3: The molecular circadian clock in mammals is formed by interlocking transcription–translation feedback loops.
Fig. 4: Peripheral clocks in Drosophila melanogaster.
Fig. 5: The central clock and selected peripheral clocks in humans.

References

  1. 1.

    Hurd, M. W. & Ralph, M. R. The significance of circadian organization for longevity in the golden hamster. J. Biol. Rhythm. 13, 430–436 (1998).

    CAS  Google Scholar 

  2. 2.

    Martino, T. A. et al. Circadian rhythm disorganization produces profound cardiovascular and renal disease in hamsters. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R1675–R1683 (2008).

    CAS  PubMed  Google Scholar 

  3. 3.

    Ouyang, Y., Andersson, C. R., Kondo, T., Golden, S. S. & Johnson, C. H. Resonating circadian clocks enhance fitness in cyanobacteria. Proc. Natl Acad. Sci. USA 95, 8660–8664 (1998).

    CAS  PubMed  Google Scholar 

  4. 4.

    Pittendrigh, C. S. & Minis, D. H. Circadian systems: longevity as a function of circadian resonance in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 69, 1537–1539 (1972). This study presents a theoretical framework for the adaptive advantage of having a circadian clock.

    CAS  PubMed  Google Scholar 

  5. 5.

    Woelfle, M. A., Ouyang, Y., Phanvijhitsiri, K. & Johnson, C. H. The adaptive value of circadian clocks: an experimental assessment in cyanobacteria. Curr. Biol. 14, 1481–1486 (2004).

    CAS  PubMed  Google Scholar 

  6. 6.

    Pittendrigh, C. S. Temporal organization: reflections of a Darwinian clock-watcher. Annu. Rev. Physiol. 55, 16–54 (1993).

    CAS  PubMed  Google Scholar 

  7. 7.

    Sehgal, A. Physiology flies with time. Cell 171, 1232–1235 (2017).

    CAS  PubMed  Google Scholar 

  8. 8.

    Roenneberg, T. & Merrow, M. The circadian clock and human health. Curr. Biol. 26, R432–R443 (2016).

    CAS  PubMed  Google Scholar 

  9. 9.

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

    CAS  PubMed  Google Scholar 

  10. 10.

    Zhang, R., Lahens, N. F., Ballance, H. I., Hughes, M. E. & Hogenesch, J. B. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc. Natl Acad. Sci. USA 111, 16219–16224 (2014).

    CAS  PubMed  Google Scholar 

  11. 11.

    Konopka, R. J. & Benzer, S. Clock mutants of Drosophila melanogaster. Proc. Natl Acad. Sci. USA 68, 2112–2116 (1971). This landmark paper describes the discovery of the first D. melanogaster clock mutants.

    CAS  PubMed  Google Scholar 

  12. 12.

    Bargiello, T. A., Jackson, F. R. & Young, M. W. Restoration of circadian behavioural rhythms by gene transfer in Drosophila. Nature 312, 752–754 (1984).

    CAS  PubMed  Google Scholar 

  13. 13.

    Zehring, W. A. et al. P-element transformation with period locus DNA restores rhythmicity to mutant, arrhythmic Drosophila melanogaster. Cell 39, 369–376 (1984). Together with Bargiello et al. (1984), this paper describes the first cloning of a clock gene, period, in D. melanogaster.

    CAS  PubMed  Google Scholar 

  14. 14.

    Axelrod, S., Saez, L. & Young, M. W. Studying circadian rhythm and sleep using genetic screens in Drosophila. Methods Enzymol. 551, 3–27 (2015).

    CAS  PubMed  Google Scholar 

  15. 15.

    Sehgal, A., Price, J. L., Man, B. & Young, M. W. Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless. Science 263, 1603–1606 (1994).

    CAS  PubMed  Google Scholar 

  16. 16.

    Allada, R., White, N. E., So, W. V., Hall, J. C. & Rosbash, M. A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless. Cell 93, 791–804 (1998).

    CAS  PubMed  Google Scholar 

  17. 17.

    Rutila, J. E. et al. CYCLE is a second bHLH–PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless. Cell 93, 805–814 (1998).

    CAS  PubMed  Google Scholar 

  18. 18.

    Ceriani, M. F. et al. Light-dependent sequestration of TIMELESS by CRYPTOCHROME. Science 285, 553–556 (1999).

    CAS  PubMed  Google Scholar 

  19. 19.

    Koh, K., Zheng, X. & Sehgal, A. JETLAG resets the Drosophila circadian clock by promoting light-induced degradation of TIMELESS. Science 312, 1809–1812 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Peschel, N., Chen, K. F., Szabo, G. & Stanewsky, R. Light-dependent interactions between the Drosophila circadian clock factors cryptochrome, jetlag, and timeless. Curr. Biol. 19, 241–247 (2009).

    CAS  PubMed  Google Scholar 

  21. 21.

    Kloss, B. et al. The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iε. Cell 94, 97–107 (1998).

    CAS  PubMed  Google Scholar 

  22. 22.

    Price, J. L. et al. double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94, 83–95 (1998). Together with Kloss et al. (1998), this paper is the first to describe a role for protein phosphorylation in circadian clocks.

    CAS  PubMed  Google Scholar 

  23. 23.

    Grima, B. et al. The F-box protein slimb controls the levels of clock proteins period and timeless. Nature 420, 178–182 (2002).

    CAS  PubMed  Google Scholar 

  24. 24.

    Ko, H. W., Jiang, J. & Edery, I. Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime. Nature 420, 673–678 (2002).

    CAS  PubMed  Google Scholar 

  25. 25.

    Kula-Eversole, E. et al. Surprising gene expression patterns within and between PDF-containing circadian neurons in Drosophila. Proc. Natl Acad. Sci. USA 107, 13497–13502 (2010).

    PubMed  Google Scholar 

  26. 26.

    Ceriani, M. F. et al. Genome-wide expression analysis in Drosophila reveals genes controlling circadian behavior. J. Neurosci. 22, 9305–9319 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

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

    CAS  PubMed  Google Scholar 

  28. 28.

    Hughes, M. E., Grant, G. R., Paquin, C., Qian, J. & Nitabach, M. N. Deep sequencing the circadian and diurnal transcriptome of Drosophila brain. Genome Res. 22, 1266–1281 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Keegan, K. P., Pradhan, S., Wang, J. P. & Allada, R. Meta-analysis of Drosophila circadian microarray studies identifies a novel set of rhythmically expressed genes. PLOS Comput. Biol. 3, e208 (2007).

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    McDonald, M. J. & Rosbash, M. Microarray analysis and organization of circadian gene expression in Drosophila. Cell 107, 567–578 (2001). Together with Claridge-Chang et al. (2001), this paper is the first to systematically analyse circadian gene expression in D. melanogaster.

    CAS  PubMed  Google Scholar 

  31. 31.

    Ueda, H. R. et al. Genome-wide transcriptional orchestration of circadian rhythms in Drosophila. J. Biol. Chem. 277, 14048–14052 (2002).

    CAS  PubMed  Google Scholar 

  32. 32.

    Wijnen, H., Naef, F., Boothroyd, C., Claridge-Chang, A. & Young, M. W. Control of daily transcript oscillations in Drosophila by light and the circadian clock. PLOS Genet. 2, e39 (2006).

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Xu, K., DiAngelo, J. R., Hughes, M. E., Hogenesch, J. B. & Sehgal, A. The circadian clock interacts with metabolic physiology to influence reproductive fitness. Cell Metab. 13, 639–654 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Cyran, S. A. et al. vrille, Pdp1, and dClock form a second feedback loop in the Drosophila circadian clock. Cell 112, 329–341 (2003).

    CAS  PubMed  Google Scholar 

  35. 35.

    Kim, E. Y. et al. Drosophila CLOCK protein is under posttranscriptional control and influences light-induced activity. Neuron 34, 69–81 (2002).

    CAS  PubMed  Google Scholar 

  36. 36.

    Zheng, X. et al. An isoform-specific mutant reveals a role of PDP1 epsilon in the circadian oscillator. J. Neurosci. 29, 10920–10927 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Renn, S. C., Park, J. H., Rosbash, M., Hall, J. C. & Taghert, P. H. A pdf neuropeptide gene mutation and ablation of PDF neurons each cause severe abnormalities of behavioral circadian rhythms in Drosophila. Cell 99, 791–802 (1999). This study describes the discovery that the neuropeptide PDF is required for circadian locomotor rhythms in D. melanogaster.

    CAS  PubMed  Google Scholar 

  38. 38.

    Kadener, S., Menet, J. S., Schoer, R. & Rosbash, M. Circadian transcription contributes to core period determination in Drosophila. PLOS Biol. 6, e119 (2008).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Zhao, J. et al. Drosophila clock can generate ectopic circadian clocks. Cell 113, 755–766 (2003).

    CAS  PubMed  Google Scholar 

  40. 40.

    Smith, R. F. & Konopka, R. J. Effects of dosage alterations at the per locus on the period of the circadian clock of Drosophila. Mol. Gen. Genet. 185, 30–36 (1982).

    Google Scholar 

  41. 41.

    Kadener, S., Stoleru, D., McDonald, M., Nawathean, P. & Rosbash, M. Clockwork Orange is a transcriptional repressor and a new Drosophila circadian pacemaker component. Genes Dev. 21, 1675–1686 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Lim, C. et al. Clockwork orange encodes a transcriptional repressor important for circadian-clock amplitude in Drosophila. Curr. Biol. 17, 1082–1089 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Richier, B., Michard-Vanhee, C., Lamouroux, A., Papin, C. & Rouyer, F. The clockwork orange Drosophila protein functions as both an activator and a repressor of clock gene expression. J. Biol. Rhythm. 23, 103–116 (2008).

    CAS  Google Scholar 

  44. 44.

    Kadener, S. et al. A role for microRNAs in the Drosophila circadian clock. Genes Dev. 23, 2179–2191 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Chen, W. et al. Regulation of Drosophila circadian rhythms by miRNA let-7 is mediated by a regulatory cycle. Nat. Commun. 5, 5549 (2014).

    CAS  PubMed  Google Scholar 

  46. 46.

    Chen, X. & Rosbash, M. mir-276a strengthens Drosophila circadian rhythms by regulating timeless expression. Proc. Natl Acad. Sci. USA 113, E2965–E2972 (2016).

    CAS  PubMed  Google Scholar 

  47. 47.

    Grima, B. et al. PERIOD-controlled deadenylation of the timeless transcript in the Drosophila circadian clock. Proc. Natl Acad. Sci. USA 116, 5721–5726 (2019).

    CAS  PubMed  Google Scholar 

  48. 48.

    Lim, C. et al. The novel gene twenty-four defines a critical translational step in the Drosophila clock. Nature 470, 399–403 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Lim, C. & Allada, R. ATAXIN-2 activates PERIOD translation to sustain circadian rhythms in Drosophila. Science 340, 875–879 (2013).

    CAS  PubMed  Google Scholar 

  50. 50.

    Zhang, Y., Ling, J., Yuan, C., Dubruille, R. & Emery, P. A role for Drosophila ATX2 in activation of PER translation and circadian behavior. Science 340, 879–882 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Menet, J. S., Abruzzi, K. C., Desrochers, J., Rodriguez, J. & Rosbash, M. Dynamic PER repression mechanisms in the Drosophila circadian clock: from on-DNA to off-DNA. Genes Dev. 24, 358–367 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Yu, W., Zheng, H., Price, J. L. & Hardin, P. E. DOUBLETIME plays a noncatalytic role to mediate CLOCK phosphorylation and repress CLOCK-dependent transcription within the Drosophila circadian clock. Mol. Cell Biol. 29, 1452–1458 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Yu, W., Houl, J. H. & Hardin, P. E. NEMO kinase contributes to core period determination by slowing the pace of the Drosophila circadian oscillator. Curr. Biol. 21, 756–761 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Rothenfluh, A., Abodeely, M. & Young, M. W. Short-period mutations of per affect a double-time-dependent step in the Drosophila circadian clock. Curr. Biol. 10, 1399–1402 (2000).

    CAS  PubMed  Google Scholar 

  55. 55.

    Fan, J. Y. et al. Noncanonical FK506-binding protein BDBT binds DBT to enhance its circadian function and forms foci at night. Neuron 80, 984–996 (2013).

    CAS  PubMed  Google Scholar 

  56. 56.

    Venkatesan, A., Fan, J. Y., Nauman, C. & Price, J. L. A Doubletime nuclear localization signal mediates an interaction with Bride of Doubletime to promote circadian function. J. Biol. Rhythm. 30, 302–317 (2015).

    CAS  Google Scholar 

  57. 57.

    Sathyanarayanan, S., Zheng, X., Xiao, R. & Sehgal, A. Posttranslational regulation of Drosophila PERIOD protein by protein phosphatase 2A. Cell 116, 603–615 (2004).

    CAS  PubMed  Google Scholar 

  58. 58.

    Fang, Y., Sathyanarayanan, S. & Sehgal, A. Post-translational regulation of the Drosophila circadian clock requires protein phosphatase 1 (PP1). Genes Dev. 21, 1506–1518 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Jang, A. R., Moravcevic, K., Saez, L., Young, M. W. & Sehgal, A. Drosophila TIM binds importin α1, and acts as an adapter to transport PER to the nucleus. PLOS Genet. 11, e1004974 (2015).

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    Martinek, S., Inonog, S., Manoukian, A. S. & Young, M. W. A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock. Cell 105, 769–779 (2001).

    CAS  PubMed  Google Scholar 

  61. 61.

    Top, D., Harms, E., Syed, S., Adams, E. L. & Saez, L. GSK-3 and CK2 kinases converge on Timeless to regulate the master clock. Cell Rep. 16, 357–367 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Zeng, H., Qian, Z., Myers, M. P. & Rosbash, M. A light-entrainment mechanism for the Drosophila circadian clock. Nature 380, 129–135 (1996).

    CAS  PubMed  Google Scholar 

  63. 63.

    Meyer, P., Saez, L. & Young, M. W. PER–TIM interactions in living Drosophila cells: an interval timer for the circadian clock. Science 311, 226–229 (2006).

    CAS  PubMed  Google Scholar 

  64. 64.

    Kim, E. Y. et al. A role for O-GlcNAcylation in setting circadian clock speed. Genes Dev. 26, 490–502 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Li, Y. H. et al. O-GlcNAcylation of PERIOD regulates its interaction with CLOCK and timing of circadian transcriptional repression. PLOS Genet. 15, e1007953 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    van der Horst, G. T. et al. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398, 627–630 (1999).

    PubMed  Google Scholar 

  67. 67.

    Preitner, N. et al. The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251–260 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Sato, T. K. et al. A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 43, 527–537 (2004).

    CAS  PubMed  Google Scholar 

  69. 69.

    Ueda, H. R. et al. A transcription factor response element for gene expression during circadian night. Nature 418, 534–539 (2002).

    CAS  PubMed  Google Scholar 

  70. 70.

    Gachon, F. et al. The loss of circadian PAR bZip transcription factors results in epilepsy. Genes Dev. 18, 1397–1412 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Mitsui, S., Yamaguchi, S., Matsuo, T., Ishida, Y. & Okamura, H. Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism. Genes Dev. 15, 995–1006 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Somyajit, K. et al. Redox-sensitive alteration of replisome architecture safeguards genome integrity. Science 358, 797–802 (2017).

    CAS  PubMed  Google Scholar 

  73. 73.

    Barnes, J. W. et al. Requirement of mammalian Timeless for circadian rhythmicity. Science 302, 439–442 (2003).

    CAS  PubMed  Google Scholar 

  74. 74.

    Engelen, E. et al. Mammalian TIMELESS is involved in period determination and DNA damage-dependent phase advancing of the circadian clock. PLOS ONE 8, e56623 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Anafi, R. C. et al. Machine learning helps identify CHRONO as a circadian clock component. PLOS Biol. 12, e1001840 (2014).

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Goriki, A. et al. A novel protein, CHRONO, functions as a core component of the mammalian circadian clock. PLOS Biol. 12, e1001839 (2014).

    PubMed  PubMed Central  Google Scholar 

  77. 77.

    Annayev, Y. et al. Gene model 129 (Gm129) encodes a novel transcriptional repressor that modulates circadian gene expression. J. Biol. Chem. 289, 5013–5024 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Mure, L. S. et al. Diurnal transcriptome atlas of a primate across major neural and peripheral tissues. Science 359, eaao0318 (2018). This article presents the first atlas of circadian gene expression from a diurnal primate.

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Michael, A. K. et al. Cancer/testis antigen PASD1 silences the circadian clock. Mol. Cell 58, 743–754 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Koike, N. et al. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science 338, 349–354 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Menet, J. S., Rodriguez, J., Abruzzi, K. C. & Rosbash, M. Nascent-Seq reveals novel features of mouse circadian transcriptional regulation. eLife 1, e00011 (2012).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Fang, B. et al. Circadian enhancers coordinate multiple phases of rhythmic gene transcription in vivo. Cell 159, 1140–1152 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Kim, Y. H. et al. Rev-erbα dynamically modulates chromatin looping to control circadian gene transcription. Science 359, 1274–1277 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Mermet, J. et al. Clock-dependent chromatin topology modulates circadian transcription and behavior. Genes Dev. 32, 347–358 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Fustin, J. M. et al. RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell 155, 793–806 (2013).

    CAS  PubMed  Google Scholar 

  86. 86.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Lowrey, P. L. et al. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288, 483–492 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Maier, B. et al. A large-scale functional RNAi screen reveals a role for CK2 in the mammalian circadian clock. Genes Dev. 23, 708–718 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Meng, Q. J. et al. Setting clock speed in mammals: the CK1ε tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins. Neuron 58, 78–88 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Toh, K. L. et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291, 1040–1043 (2001). This paper describes the discovery of a PER2 mutation in human familial advanced sleep phase disorder.

    CAS  PubMed  Google Scholar 

  91. 91.

    Tsuchiya, Y. et al. Involvement of the protein kinase CK2 in the regulation of mammalian circadian rhythms. Sci. Signal 2, ra26 (2009).

    PubMed  Google Scholar 

  92. 92.

    Vanselow, K. et al. Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS). Genes Dev. 20, 2660–2672 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Xu, Y. et al. Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell 128, 59–70 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Zhou, M., Kim, J. K., Eng, G. W., Forger, D. B. & Virshup, D. M. A Period2 phosphoswitch regulates and temperature compensates circadian period. Mol. Cell 60, 77–88 (2015).

    PubMed  Google Scholar 

  95. 95.

    Ohsaki, K. et al. The role of β-TrCP1 and β-TrCP2 in circadian rhythm generation by mediating degradation of clock protein PER2. J. Biochem. 144, 609–618 (2008).

    CAS  PubMed  Google Scholar 

  96. 96.

    Shirogane, T., Jin, J., Ang, X. L. & Harper, J. W. SCFβ-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein. J. Biol. Chem. 280, 26863–26872 (2005).

    CAS  PubMed  Google Scholar 

  97. 97.

    Narasimamurthy, R. et al. CK1δ/ε protein kinase primes the PER2 circadian phosphoswitch. Proc. Natl Acad. Sci. USA 115, 5986–5991 (2018).

    CAS  PubMed  Google Scholar 

  98. 98.

    Kaasik, K. et al. Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock. Cell Metab. 17, 291–302 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Liu, J. et al. Distinct control of PERIOD2 degradation and circadian rhythms by the oncoprotein and ubiquitin ligase MDM2. Sci. Signal 11, eaau0715 (2018).

    PubMed  Google Scholar 

  101. 101.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Busino, L. et al. SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. Science 316, 900–904 (2007).

    CAS  PubMed  Google Scholar 

  103. 103.

    Godinho, S. I. et al. The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science 316, 897–900 (2007).

    CAS  PubMed  Google Scholar 

  104. 104.

    Hirano, A. et al. FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes. Cell 152, 1106–1118 (2013).

    CAS  PubMed  Google Scholar 

  105. 105.

    Saran, A. R., Kalinowska, D., Oh, S., Janknecht, R. & DiTacchio, L. JMJD5 links CRY1 function and proteasomal degradation. PLOS Biol. 16, e2006145 (2018).

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Siepka, S. M. et al. Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression. Cell 129, 1011–1023 (2007). Together with Busino et al. (2007) and Godinho et al. (2007), this paper shows that the E3 ubiquitin ligase FBXL3 controls the circadian period length through degradation of the CRY proteins.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Yoo, S. H. et al. Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Cell 152, 1091–1105 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Gao, P. et al. Phosphorylation of the cryptochrome 1 C-terminal tail regulates circadian period length. J. Biol. Chem. 288, 35277–35286 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Hirano, A. et al. A Cryptochrome 2 mutation yields advanced sleep phase in humans. eLife 5, e16695 (2016).

    PubMed  PubMed Central  Google Scholar 

  110. 110.

    Hirota, T. et al. Identification of small molecule activators of cryptochrome. Science 337, 1094–1097 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Khan, S. K. et al. Identification of a novel cryptochrome differentiating domain required for feedback repression in circadian clock function. J. Biol. Chem. 287, 25917–25926 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Ode, K. L. et al. Knockout-rescue embryonic stem cell-derived mouse reveals circadian-period control by quality and quantity of CRY1. Mol. Cell 65, 176–190 (2017).

    CAS  PubMed  Google Scholar 

  113. 113.

    Oshima, T. et al. C–H activation generates period-shortening molecules that target cryptochrome in the mammalian circadian clock. Angew Chem. Int. Ed. Engl. 54, 7193–7197 (2015).

    CAS  PubMed  Google Scholar 

  114. 114.

    Patke, A. et al. Mutation of the human circadian clock gene CRY1 in familial delayed sleep phase disorder. Cell 169, 203–215.e13 (2017). This paper describes the discovery of a gain-of-function CRY1 variant in human familial delayed sleep phase disorder.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Hirano, A., Braas, D., Fu, Y. H. & Ptacek, L. J. FAD regulates CRYPTOCHROME protein stability and circadian clock in mice. Cell Rep. 19, 255–266 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Correia, S. P. et al. The circadian E3 ligase complex SCF(FBXL3+CRY) targets TLK2. Sci. Rep. 9, 198 (2019).

    PubMed  PubMed Central  Google Scholar 

  117. 117.

    Huber, A. L. et al. CRY2 and FBXL3 cooperatively degrade c-MYC. Mol. Cell 64, 774–789 (2016). This paper shows that CRY2 can act as a cofactor of FBXL3 in the degradation of MYC.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Sahar, S., Zocchi, L., Kinoshita, C., Borrelli, E. & Sassone-Corsi, P. Regulation of BMAL1 protein stability and circadian function by GSK3β-mediated phosphorylation. PLOS ONE 5, e8561 (2010).

    PubMed  PubMed Central  Google Scholar 

  119. 119.

    Tamaru, T. et al. CRY drives cyclic CK2-mediated BMAL1 phosphorylation to control the mammalian circadian clock. PLOS Biol. 13, e1002293 (2015).

    PubMed  PubMed Central  Google Scholar 

  120. 120.

    Tamaru, T. et al. CK2α phosphorylates BMAL1 to regulate the mammalian clock. Nat. Struct. Mol. Biol. 16, 446–448 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Cardone, L. et al. Circadian clock control by SUMOylation of BMAL1. Science 309, 1390–1394 (2005).

    CAS  PubMed  Google Scholar 

  122. 122.

    Gossan, N. C. et al. The E3 ubiquitin ligase UBE3A is an integral component of the molecular circadian clock through regulating the BMAL1 transcription factor. Nucleic Acids Res. 42, 5765–5775 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Lee, J. et al. Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex. Mol. Cell Biol. 28, 6056–6065 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

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

    CAS  PubMed  Google Scholar 

  125. 125.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Petkau, N., Budak, H., Zhou, X., Oster, H. & Eichele, G. Acetylation of BMAL1 by TIP60 controls BRD4–P-TEFb recruitment to circadian promoters. eLife 8 (2019).

  127. 127.

    Yin, L., Joshi, S., Wu, N., Tong, X. & Lazar, M. A. E3 ligases Arf-bp1 and Pam mediate lithium-stimulated degradation of the circadian heme receptor Rev-erbα. Proc. Natl Acad. Sci. USA 107, 11614–11619 (2010).

    CAS  PubMed  Google Scholar 

  128. 128.

    Yin, L., Wang, J., Klein, P. S. & Lazar, M. A. Nuclear receptor Rev-erbα is a critical lithium-sensitive component of the circadian clock. Science 311, 1002–1005 (2006).

    CAS  PubMed  Google Scholar 

  129. 129.

    DeBruyne, J. P., Baggs, J. E., Sato, T. K. & Hogenesch, J. B. Ubiquitin ligase Siah2 regulates RevErbα degradation and the mammalian circadian clock. Proc. Natl Acad. Sci. USA 112, 12420–12425 (2015).

    CAS  PubMed  Google Scholar 

  130. 130.

    Zhao, X. et al. Circadian amplitude regulation via FBXW7-targeted REV-ERBα degradation. Cell 165, 1644–1657 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Aryal, R. P. et al. Macromolecular assemblies of the mammalian circadian clock. Mol. Cell 67, 770–782 e776 (2017). This study presents the purification and characterization of macromolecular clock protein assemblies.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Chiou, Y. Y. et al. Mammalian Period represses and de-represses transcription by displacing CLOCK–BMAL1 from promoters in a Cryptochrome-dependent manner. Proc. Natl Acad. Sci. USA 113, E6072–E6079 (2016).

    CAS  PubMed  Google Scholar 

  133. 133.

    Duong, H. A. & Weitz, C. J. Temporal orchestration of repressive chromatin modifiers by circadian clock Period complexes. Nat. Struct. Mol. Biol. 21, 126–132 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Xu, H. et al. Cryptochrome 1 regulates the circadian clock through dynamic interactions with the BMAL1 C terminus. Nat. Struct. Mol. Biol. 22, 476–484 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Ye, R. et al. Dual modes of CLOCK:BMAL1 inhibition mediated by Cryptochrome and Period proteins in the mammalian circadian clock. Genes Dev. 28, 1989–1998 (2014). This paper shows that mammalian CRY proteins can inhibit the transcriptional activity of CLOCK–BMAL1 either through direct blocking of DNA binding or through displacement of CLOCK–BMAL1 from promoters.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Ye, R., Selby, C. P., Ozturk, N., Annayev, Y. & Sancar, A. Biochemical analysis of the canonical model for the mammalian circadian clock. J. Biol. Chem. 286, 25891–25902 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    King, A. N. & Sehgal, A. Molecular and circuit mechanisms mediating circadian clock output in the Drosophila brain. Eur. J. Neurosci. https://doi.org/10.1111/ejn.14092 (2018).

  138. 138.

    Dissel, S. et al. The logic of circadian organization in Drosophila. Curr. Biol. 24, 2257–2266 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Yao, Z., Bennett, A. J., Clem, J. L. & Shafer, O. T. The Drosophila clock neuron network features diverse coupling modes and requires network-wide coherence for robust circadian rhythms. Cell Rep. 17, 2873–2881 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Yao, Z. & Shafer, O. T. The Drosophila circadian clock is a variably coupled network of multiple peptidergic units. Science 343, 1516–1520 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Liang, X., Holy, T. E. & Taghert, P. H. Synchronous Drosophila circadian pacemakers display nonsynchronous Ca2+ rhythms in vivo. Science 351, 976–981 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Dubowy, C. & Sehgal, A. Circadian rhythms and sleep in Drosophila melanogaster. Genetics 205, 1373–1397 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Muraro, N. I., Pirez, N. & Ceriani, M. F. The circadian system: plasticity at many levels. Neuroscience 247, 280–293 (2013).

    CAS  PubMed  Google Scholar 

  144. 144.

    Gorostiza, E. A., Depetris-Chauvin, A., Frenkel, L., Pirez, N. & Ceriani, M. F. Circadian pacemaker neurons change synaptic contacts across the day. Curr. Biol. 24, 2161–2167 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Gorska-Andrzejak, J. Glia-related circadian plasticity in the visual system of Diptera. Front. Physiol. 4, 36 (2013).

    PubMed  PubMed Central  Google Scholar 

  146. 146.

    Jackson, F. R., Ng, F. S., Sengupta, S., You, S. & Huang, Y. Glial cell regulation of rhythmic behavior. Methods Enzymol. 552, 45–73 (2015).

    CAS  PubMed  Google Scholar 

  147. 147.

    Franco, D. L., Frenkel, L. & Ceriani, M. F. The underlying genetics of Drosophila circadian behaviors. Physiology 33, 50–62 (2018).

    CAS  PubMed  Google Scholar 

  148. 148.

    Stoleru, D. et al. The Drosophila circadian network is a seasonal timer. Cell 129, 207–219 (2007).

    CAS  PubMed  Google Scholar 

  149. 149.

    Ralph, M. R., Foster, R. G., Davis, F. C. & Menaker, M. Transplanted suprachiasmatic nucleus determines circadian period. Science 247, 975–978 (1990). This paper shows that reciprocal SCN transplantation between normal and short-period mutant hamsters switches their circadian period.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Silver, R., LeSauter, J., Tresco, P. A. & Lehman, M. N. A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms. Nature 382, 810–813 (1996).

    CAS  PubMed  Google Scholar 

  151. 151.

    Schibler, U. et al. Clock-talk: interactions between central and peripheral circadian oscillators in mammals. Cold Spring Harb. Symp. Quant. Biol. 80, 223–232 (2015).

    PubMed  Google Scholar 

  152. 152.

    DeBruyne, J. P., Weaver, D. R. & Reppert, S. M. CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nat. Neurosci. 10, 543–545 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Landgraf, D., Wang, L. L., Diemer, T. & Welsh, D. K. NPAS2 compensates for loss of CLOCK in peripheral circadian oscillators. PLOS Genet. 12, e1005882 (2016).

    PubMed  PubMed Central  Google Scholar 

  154. 154.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Jones, J. R., Tackenberg, M. C. & McMahon, D. G. Manipulating circadian clock neuron firing rate resets molecular circadian rhythms and behavior. Nat. Neurosci. 18, 373–375 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Hastings, M. H., Maywood, E. S. & Brancaccio, M. Generation of circadian rhythms in the suprachiasmatic nucleus. Nat. Rev. Neurosci. 19, 453–469 (2018).

    CAS  PubMed  Google Scholar 

  157. 157.

    Brancaccio, M. et al. Cell-autonomous clock of astrocytes drives circadian behavior in mammals. Science 363, 187–192 (2019). This paper shows that restoring clock function in SCN astrocytes is sufficient to restore locomotor rhythms in clock-less mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Brancaccio, M., Patton, A. P., Chesham, J. E., Maywood, E. S. & Hastings, M. H. Astrocytes control circadian timekeeping in the suprachiasmatic nucleus via glutamatergic signaling. Neuron 93, 1420–1435.e5(2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Tso, C. F. et al. Astrocytes regulate daily rhythms in the suprachiasmatic nucleus and behavior. Curr. Biol. 27, 1055–1061 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160.

    Selcho, M. et al. Central and peripheral clocks are coupled by a neuropeptide pathway in Drosophila. Nat. Commun. 8, 15563 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Chatterjee, A., Tanoue, S., Houl, J. H. & Hardin, P. E. Regulation of gustatory physiology and appetitive behavior by the Drosophila circadian clock. Curr. Biol. 20, 300–309 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Giebultowicz, J. M. & Hege, D. M. Circadian clock in Malpighian tubules. Nature 386, 664–664 (1997).

    CAS  PubMed  Google Scholar 

  163. 163.

    Ivanchenko, M., Stanewsky, R. & Giebultowicz, J. M. Circadian photoreception in Drosophila: functions of cryptochrome in peripheral and central clocks. J. Biol. Rhythm. 16, 205–215 (2001).

    CAS  Google Scholar 

  164. 164.

    Plautz, J. D., Kaneko, M., Hall, J. C. & Kay, S. A. Independent photoreceptive circadian clocks throughout Drosophila. Science 278, 1632–1635 (1997).

    CAS  PubMed  Google Scholar 

  165. 165.

    Di Cara, F. & King-Jones, K. The circadian clock is a key driver of steroid hormone production in Drosophila. Curr. Biol. 26, 2469–2477 (2016).

    PubMed  Google Scholar 

  166. 166.

    Sehgal, A. in A Time for Metabolism and Hormones (eds Sassone-Corsi, P. & Christen, Y.) 33–40 (Springer, 2016).

  167. 167.

    Erion, R., King, A. N., Wu, G., Hogenesch, J. B. & Sehgal, A. Neural clocks and Neuropeptide F/Y regulate circadian gene expression in a peripheral metabolic tissue. eLife 5, e13552 (2016).

    PubMed  PubMed Central  Google Scholar 

  168. 168.

    Giebultowicz, J. M., Stanewsky, R., Hall, J. C. & Hege, D. M. Transplanted Drosophila excretory tubules maintain circadian clock cycling out of phase with the host. Curr. Biol. 10, 107–110 (2000).

    CAS  PubMed  Google Scholar 

  169. 169.

    Borbely, A. A. & Achermann, P. Sleep homeostasis and models of sleep regulation. J. Biol. Rhythm. 14, 557–568 (1999).

    CAS  Google Scholar 

  170. 170.

    Ly, S., Pack, A. I. & Naidoo, N. The neurobiological basis of sleep: insights from Drosophila. Neurosci. Biobehav. Rev. 87, 67–86 (2018).

    PubMed  PubMed Central  Google Scholar 

  171. 171.

    Hendricks, J. C. et al. Rest in Drosophila is a sleep-like state. Neuron 25, 129–138 (2000).

    CAS  PubMed  Google Scholar 

  172. 172.

    Rogulja, D. & Young, M. W. Control of sleep by cyclin A and its regulator. Science 335, 1617–1621 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Shi, M., Yue, Z., Kuryatov, A., Lindstrom, J. M. & Sehgal, A. Identification of Redeye, a new sleep-regulating protein whose expression is modulated by sleep amount. eLife 3, e01473 (2014).

    PubMed  PubMed Central  Google Scholar 

  174. 174.

    Stavropoulos, N. & Young, M. W. insomniac and Cullin-3 regulate sleep and wakefulness in Drosophila. Neuron 72, 964–976 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Liu, S. et al. WIDE AWAKE mediates the circadian timing of sleep onset. Neuron 82, 151–166 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Franken, P. A role for clock genes in sleep homeostasis. Curr. Opin. Neurobiol. 23, 864–872 (2013).

    CAS  PubMed  Google Scholar 

  177. 177.

    Hendricks, J. C. et al. Gender dimorphism in the role of cycle (BMAL1) in rest, rest regulation, and longevity in Drosophila melanogaster. J. Biol. Rhythm. 18, 12–25 (2003).

    CAS  Google Scholar 

  178. 178.

    Shaw, P. J., Tononi, G., Greenspan, R. J. & Robinson, D. F. Stress response genes protect against lethal effects of sleep deprivation in Drosophila. Nature 417, 287–291 (2002).

    CAS  PubMed  Google Scholar 

  179. 179.

    Keene, A. C. et al. Clock and cycle limit starvation-induced sleep loss in Drosophila. Curr. Biol. 20, 1209–1215 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Guo, F. et al. Circadian neuron feedback controls the Drosophila sleep–activity profile. Nature 536, 292–297 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Kunst, M. et al. Calcitonin gene-related peptide neurons mediate sleep-specific circadian output in Drosophila. Curr. Biol. 24, 2652–2664 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Yadlapalli, S. et al. Circadian clock neurons constantly monitor environmental temperature to set sleep timing. Nature 555, 98–102 (2018).

    CAS  PubMed  Google Scholar 

  183. 183.

    Krupp, J. J. et al. Pigment-dispersing factor modulates pheromone production in clock cells that influence mating in Drosophila. Neuron 79, 54–68 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    Wagner, A. E., Van Nest, B. N., Hobbs, C. N. & Moore, D. Persistence, reticence and the management of multiple time memories by forager honey bees. J. Exp. Biol. 216, 1131–1141 (2013).

    PubMed  Google Scholar 

  185. 185.

    Chouhan, N. S., Wolf, R., Helfrich-Forster, C. & Heisenberg, M. Flies remember the time of day. Curr. Biol. 25, 1619–1624 (2015).

    CAS  PubMed  Google Scholar 

  186. 186.

    Zhang, S. L., Yue, Z., Arnold, D. M., Artiushin, G. & Sehgal, A. A circadian clock in the blood–brain barrier regulates xenobiotic efflux. Cell 173, 130–139.e10 (2018). This paper shows that receptor-mediated drug transport through the D. melanogaster blood–brain barrier exhibits circadian rhythmicity.

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Balsalobre, A., Damiola, F. & Schibler, U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93, 929–937 (1998). This paper describes the discovery of circadian rhythms in cultured fibroblast cell lines.

    CAS  Google Scholar 

  188. 188.

    Yoo, S. H. et al. PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc. Natl Acad. Sci. USA 101, 5339–5346 (2004). This study presents ex vivo measurements of peripheral clock rhythms using a PER2–luciferase knock-in reporter.

    CAS  PubMed  Google Scholar 

  189. 189.

    Kowalska, E., Moriggi, E., Bauer, C., Dibner, C. & Brown, S. A. The circadian clock starts ticking at a developmentally early stage. J. Biol. Rhythm. 25, 442–449 (2010).

    Google Scholar 

  190. 190.

    Paulose, J. K., Rucker, E. B. 3rd & Cassone, V. M. Toward the beginning of time: circadian rhythms in metabolism precede rhythms in clock gene expression in mouse embryonic stem cells. PLOS ONE 7, e49555 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    Yagita, K. et al. Development of the circadian oscillator during differentiation of mouse embryonic stem cells in vitro. Proc. Natl Acad. Sci. USA 107, 3846–3851 (2010).

    CAS  PubMed  Google Scholar 

  192. 192.

    McDearmon, E. L. et al. Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice. Science 314, 1304–1308 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193.

    Hoyle, N. P. et al. Circadian actin dynamics drive rhythmic fibroblast mobilization during wound healing. Sci. Transl. Med. 9, eaal2774 (2017).

    PubMed  PubMed Central  Google Scholar 

  194. 194.

    Lamia, K. A., Storch, K. F. & Weitz, C. J. Physiological significance of a peripheral tissue circadian clock. Proc. Natl Acad. Sci. USA 105, 15172–15177 (2008).

    CAS  PubMed  Google Scholar 

  195. 195.

    Marcheva, B. et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466, 627–631 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196.

    Mereness, A. L. et al. Conditional deletion of Bmal1 in ovarian theca cells disrupts ovulation in female mice. Endocrinology 157, 913–927 (2016).

    CAS  PubMed  Google Scholar 

  197. 197.

    Orozco-Solis, R. et al. The circadian clock in the ventromedial hypothalamus controls cyclic energy expenditure. Cell Metab. 23, 467–478 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198.

    Ehlen, J. C. et al. Bmal1 function in skeletal muscle regulates sleep. eLife 6, e26557 (2017).

    PubMed  PubMed Central  Google Scholar 

  199. 199.

    Ruben, M. D. et al. A database of tissue-specific rhythmically expressed human genes has potential applications in circadian medicine. Sci. Transl. Med. 10, eaat8806 (2018).

    PubMed  Google Scholar 

  200. 200.

    Yeung, J. et al. Transcription factor activity rhythms and tissue-specific chromatin interactions explain circadian gene expression across organs. Genome Res. 28, 182–191 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201.

    Jeyaraj, D. et al. Circadian rhythms govern cardiac repolarization and arrhythmogenesis. Nature 483, 96–99 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 202.

    Schroder, E. A. et al. The cardiomyocyte molecular clock regulates the circadian expression of Kcnh2 and contributes to ventricular repolarization. Heart Rhythm. 12, 1306–1314 (2015).

    PubMed  PubMed Central  Google Scholar 

  203. 203.

    Schroder, E. A. et al. The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility. Am. J. Physiol. Cell Physiol. 304, C954–C965 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204.

    Young, M. E. et al. Cardiomyocyte-specific BMAL1 plays critical roles in metabolism, signaling, and maintenance of contractile function of the heart. J. Biol. Rhythm. 29, 257–276 (2014).

    CAS  Google Scholar 

  205. 205.

    Gaddameedhi, S., Selby, C. P., Kaufmann, W. K., Smart, R. C. & Sancar, A. Control of skin cancer by the circadian rhythm. Proc. Natl Acad. Sci. USA 108, 18790–18795 (2011).

    CAS  PubMed  Google Scholar 

  206. 206.

    Geyfman, M. et al. Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis. Proc. Natl Acad. Sci. USA 109, 11758–11763 (2012).

    CAS  PubMed  Google Scholar 

  207. 207.

    Solocinski, K. & Gumz, M. L. The circadian clock in the regulation of renal rhythms. J. Biol. Rhythm. 30, 470–486 (2015).

    CAS  Google Scholar 

  208. 208.

    Zhang, L. et al. KLF15 establishes the landscape of diurnal expression in the heart. Cell Rep. 13, 2368–2375 (2015).

    CAS  PubMed  Google Scholar 

  209. 209.

    Zhang, Y. et al. HNF6 and Rev-erbα integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms. Genes Dev. 30, 1636–1644 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. 210.

    Zhang, Y. et al. Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock. Science 348, 1488–1492 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. 211.

    Jordan, S. D. et al. CRY1/2 selectively repress PPARδ and limit exercise capacity. Cell Metab. 26, 243–255.e6 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. 212.

    Kriebs, A. et al. Circadian repressors CRY1 and CRY2 broadly interact with nuclear receptors and modulate transcriptional activity. Proc. Natl Acad. Sci. USA 114, 8776–8781 (2017).

    CAS  PubMed  Google Scholar 

  213. 213.

    Lamia, K. A. et al. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 480, 552–556 (2011). This paper shows that mammalian CRY proteins bind to and regulate the activity of nuclear receptors, including the glucocorticoid receptor.

    CAS  PubMed  PubMed Central  Google Scholar 

  214. 214.

    Kato, Y., Kawamoto, T., Fujimoto, K. & Noshiro, M. DEC1/STRA13/SHARP2 and DEC2/SHARP1 coordinate physiological processes, including circadian rhythms in response to environmental stimuli. Curr. Top Dev. Biol. 110, 339–372 (2014).

    CAS  PubMed  Google Scholar 

  215. 215.

    Hogenesch, J. B., Gu, Y. Z., Jain, S. & Bradfield, C. A. The basic-helix–loop–helix–PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc. Natl Acad. Sci. USA 95, 5474–5479 (1998).

    CAS  PubMed  Google Scholar 

  216. 216.

    Wu, Y. et al. Reciprocal regulation between the circadian clock and hypoxia signaling at the genome level in mammals. Cell Metab. 25, 73–85 (2017).

    CAS  PubMed  Google Scholar 

  217. 217.

    Peek, C. B. et al. Circadian clock interaction with HIF1α mediates oxygenic metabolism and anaerobic glycolysis in skeletal muscle. Cell Metab. 25, 86–92 (2017).

    CAS  PubMed  Google Scholar 

  218. 218.

    Dimova, E. Y. et al. The circadian clock protein CRY1 is a negative regulator of HIF-1α. iScience 13, 284–304 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. 219.

    Shimomura, K. et al. Usf1, a suppressor of the circadian Clock mutant, reveals the nature of the DNA-binding of the CLOCK:BMAL1 complex in mice. eLife 2, e00426 (2013).

    PubMed  PubMed Central  Google Scholar 

  220. 220.

    Hodge, B. A. et al. MYOD1 functions as a clock amplifier as well as a critical co-factor for downstream circadian gene expression in muscle. eLife 8, e43017 (2019).

    PubMed  PubMed Central  Google Scholar 

  221. 221.

    Altman, B. J. et al. MYC disrupts the circadian clock and metabolism in cancer cells. Cell Metab. 22, 1009–1019 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. 222.

    Shostak, A. et al. MYC/MIZ1-dependent gene repression inversely coordinates the circadian clock with cell cycle and proliferation. Nat. Commun. 7, 11807 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. 223.

    Beytebiere, J. R. et al. Tissue-specific BMAL1 cistromes reveal that rhythmic transcription is associated with rhythmic enhancer–enhancer interactions. Genes Dev. 33, 294–309 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. 224.

    Menet, J. S., Pescatore, S. & Rosbash, M. CLOCK:BMAL1 is a pioneer-like transcription factor. Genes Dev. 28, 8–13 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. 225.

    Sobel, J. A. et al. Transcriptional regulatory logic of the diurnal cycle in the mouse liver. PLOS Biol. 15, e2001069 (2017).

    PubMed  PubMed Central  Google Scholar 

  226. 226.

    Fonjallaz, P., Ossipow, V., Wanner, G. & Schibler, U. The two PAR leucine zipper proteins, TEF and DBP, display similar circadian and tissue-specific expression, but have different target promoter preferences. EMBO J. 15, 351–362 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. 227.

    Lopez-Molina, L., Conquet, F., Dubois-Dauphin, M. & Schibler, U. The DBP gene is expressed according to a circadian rhythm in the suprachiasmatic nucleus and influences circadian behavior. EMBO J. 16, 6762–6771 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. 228.

    Gachon, F., Olela, F. F., Schaad, O., Descombes, P. & Schibler, U. The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification. Cell Metab. 4, 25–36 (2006).

    CAS  PubMed  Google Scholar 

  229. 229.

    Qu, M., Duffy, T., Hirota, T. & Kay, S. A. Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks. Proc. Natl Acad. Sci. USA 115, E12305–E12312 (2018).

    CAS  PubMed  Google Scholar 

  230. 230.

    Ito, C. & Tomioka, K. Heterogeneity of the peripheral circadian systems in Drosophila melanogaster: a review. Front. Physiol. 7, 8 (2016).

    PubMed  PubMed Central  Google Scholar 

  231. 231.

    Myers, M. P., Wager-Smith, K., Rothenfluh-Hilfiker, A. & Young, M. W. Light-induced degradation of TIMELESS and entrainment of the Drosophila circadian clock. Science 271, 1736–1740 (1996).

    CAS  PubMed  Google Scholar 

  232. 232.

    Pittendrigh, C. S. Circadian systems. I. The driving oscillation and its assay in Drosophila pseudoobscura. Proc. Natl Acad. Sci. USA 58, 1762–1767 (1967).

    CAS  PubMed  Google Scholar 

  233. 233.

    Chaves, I. et al. The cryptochromes: blue light photoreceptors in plants and animals. Annu. Rev. Plant Biol. 62, 335–364 (2011).

    CAS  PubMed  Google Scholar 

  234. 234.

    Berndt, A. et al. A novel photoreaction mechanism for the circadian blue light photoreceptor Drosophila cryptochrome. J. Biol. Chem. 282, 13011–13021 (2007).

    CAS  PubMed  Google Scholar 

  235. 235.

    Lockley, S. W., Brainard, G. C. & Czeisler, C. A. High sensitivity of the human circadian melatonin rhythm to resetting by short wavelength light. J. Clin. Endocrinol. Metab. 88, 4502–4505 (2003).

    CAS  PubMed  Google Scholar 

  236. 236.

    Sathyanarayanan, S. et al. Identification of novel genes involved in light-dependent CRY degradation through a genome-wide RNAi screen. Genes Dev. 22, 1522–1533 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. 237.

    Lee, C., Parikh, V., Itsukaichi, T., Bae, K. & Edery, I. Resetting the Drosophila clock by photic regulation of PER and a PER–TIM complex. Science 271, 1740–1744 (1996).

    CAS  PubMed  Google Scholar 

  238. 238.

    Hunter-Ensor, M., Ousley, A. & Sehgal, A. Regulation of the Drosophila protein timeless suggests a mechanism for resetting the circadian clock by light. Cell 84, 677–685 (1996).

    CAS  PubMed  Google Scholar 

  239. 239.

    Senthilan, P. R., Grebler, R., Reinhard, N., Rieger, D. & Helfrich-Forster, C. Role of rhodopsins as circadian photoreceptors in the Drosophila melanogaster. Biology 8, E6 (2019).

    PubMed  Google Scholar 

  240. 240.

    Ni, J. D., Baik, L. S., Holmes, T. C. & Montell, C. A rhodopsin in the brain functions in circadian photoentrainment in Drosophila. Nature 545, 340–344 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. 241.

    Chen, C. et al. Drosophila Ionotropic Receptor 25a mediates circadian clock resetting by temperature. Nature 527, 516–520 (2015).

    CAS  PubMed  Google Scholar 

  242. 242.

    Simoni, A. et al. A mechanosensory pathway to the Drosophila circadian clock. Science 343, 525–528 (2014).

    CAS  PubMed  Google Scholar 

  243. 243.

    Barber, A. F., Erion, R., Holmes, T. C. & Sehgal, A. Circadian and feeding cues integrate to drive rhythms of physiology in Drosophila insulin-producing cells. Genes Dev. 30, 2596–2606 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. 244.

    Gill, S., Le, H. D., Melkani, G. C. & Panda, S. Time-restricted feeding attenuates age-related cardiac decline in Drosophila. Science 347, 1265–1269 (2015). This paper shows that diurnal feeding improves cardiac health in D. melanogaster.

    CAS  PubMed  PubMed Central  Google Scholar 

  245. 245.

    Mitchell, S. J. et al. Daily fasting improves health and survival in male mice independent of diet composition and calories. Cell Metab. 29, 221–228.e3 (2019).

    CAS  PubMed  Google Scholar 

  246. 246.

    Ulgherait, M. et al. Dietary restriction extends the lifespan of circadian mutants tim and per. Cell Metab. 24, 763–764 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. 247.

    Morioka, E., Oida, M., Tsuchida, T. & Ikeda, M. Nighttime activities and peripheral clock oscillations depend on Wolbachia endosymbionts in flies. Sci. Rep. 8, 15432 (2018).

    PubMed  PubMed Central  Google Scholar 

  248. 248.

    Yoshii, T., Hermann, C. & Helfrich-Forster, C. Cryptochrome-positive and -negative clock neurons in Drosophila entrain differentially to light and temperature. J. Biol. Rhythm. 25, 387–398 (2010).

    Google Scholar 

  249. 249.

    Harper, R. E. F., Dayan, P., Albert, J. T. & Stanewsky, R. Sensory conflict disrupts activity of the Drosophila circadian network. Cell Rep. 17, 1711–1718 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. 250.

    Kume, K. et al. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98, 193–205 (1999). This paper shows that, unlike D. melanogaster CRY, mammalian CRY1 and CRY2 act as transcriptional inhibitors of CLOCK–BMAL1.

    CAS  PubMed  Google Scholar 

  251. 251.

    Froy, O., Chang, D. C. & Reppert, S. M. Redox potential: differential roles in dCRY and mCRY1 functions. Curr. Biol. 12, 147–152 (2002).

    CAS  PubMed  Google Scholar 

  252. 252.

    Hughes, S., Jagannath, A., Hankins, M. W., Foster, R. G. & Peirson, S. N. Photic regulation of clock systems. Methods Enzymol. 552, 125–143 (2015).

    CAS  PubMed  Google Scholar 

  253. 253.

    Brown, S. A., Zumbrunn, G., Fleury-Olela, F., Preitner, N. & Schibler, U. Rhythms of mammalian body temperature can sustain peripheral circadian clocks. Curr. Biol. 12, 1574–1583 (2002).

    CAS  PubMed  Google Scholar 

  254. 254.

    Buhr, E. D., Yoo, S. H. & Takahashi, J. S. Temperature as a universal resetting cue for mammalian circadian oscillators. Science 330, 379–385 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  255. 255.

    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. 26, 567–580 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. 256.

    Tamaru, T. et al. Synchronization of circadian Per2 rhythms and HSF1-BMAL1:CLOCK interaction in mouse fibroblasts after short-term heat shock pulse. PLOS ONE 6, e24521 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. 257.

    Reinke, H. et al. Differential display of DNA-binding proteins reveals heat-shock factor 1 as a circadian transcription factor. Genes Dev. 22, 331–345 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. 258.

    Morf, J. et al. Cold-inducible RNA-binding protein modulates circadian gene expression posttranscriptionally. Science 338, 379–383 (2012).

    CAS  PubMed  Google Scholar 

  259. 259.

    Adamovich, Y., Ladeuix, B., Golik, M., Koeners, M. P. & Asher, G. Rhythmic oxygen levels reset circadian clocks through HIF1α. Cell Metab. 25, 93–101 (2017).

    CAS  PubMed  Google Scholar 

  260. 260.

    Adamovich, Y. et al. Oxygen and carbon dioxide rhythms are circadian clock controlled and differentially directed by behavioral signals. Cell Metab. 29, 1092–1103 (2019).

    CAS  PubMed  Google Scholar 

  261. 261.

    Guo, H., Brewer, J. M., Champhekar, A., Harris, R. B. & Bittman, E. L. Differential control of peripheral circadian rhythms by suprachiasmatic-dependent neural signals. Proc. Natl Acad. Sci. USA 102, 3111–3116 (2005).

    CAS  PubMed  Google Scholar 

  262. 262.

    Gerber, A. et al. Blood-borne circadian signal stimulates daily oscillations in actin dynamics and SRF activity. Cell 152, 492–503 (2013).

    CAS  PubMed  Google Scholar 

  263. 263.

    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).

    PubMed  PubMed Central  Google Scholar 

  264. 264.

    Damiola, F. et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 14, 2950–2961 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. 265.

    Greenwell, B. J. et al. Rhythmic food intake drives rhythmic gene expression more potently than the hepatic circadian clock in mice. Cell Rep. 27, 649–657.e5 (2019).

    CAS  PubMed  Google Scholar 

  266. 266.

    Izumo, M. et al. Differential effects of light and feeding on circadian organization of peripheral clocks in a forebrain Bmal1 mutant. eLife 3, e04617 (2014).

    PubMed Central  Google Scholar 

  267. 267.

    Stokkan, K. A., Yamazaki, S., Tei, H., Sakaki, Y. & Menaker, M. Entrainment of the circadian clock in the liver by feeding. Science 291, 490–493 (2001). Together with Damiola et al. (2000), this paper shows that the circadian clock in the liver is entrained by the timing of food intake.

    CAS  PubMed  PubMed Central  Google Scholar 

  268. 268.

    Vollmers, C. et al. Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proc. Natl Acad. Sci. USA 106, 21453–21458 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  269. 269.

    Marchant, E. G. & Mistlberger, R. E. Anticipation and entrainment to feeding time in intact and SCN-ablated C57BL/6j mice. Brain Res. 765, 273–282 (1997).

    CAS  PubMed  Google Scholar 

  270. 270.

    Crosby, P. et al. Insulin/IGF-1 drives PERIOD synthesis to entrain circadian rhythms with feeding time. Cell 177, 896–909 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  271. 271.

    Sato, M., Murakami, M., Node, K., Matsumura, R. & Akashi, M. The role of the endocrine system in feeding-induced tissue-specific circadian entrainment. Cell Rep. 8, 393–401 (2014).

    CAS  PubMed  Google Scholar 

  272. 272.

    Tahara, Y., Otsuka, M., Fuse, Y., Hirao, A. & Shibata, S. Refeeding after fasting elicits insulin-dependent regulation of Per2 and Rev-erbα with shifts in the liver clock. J. Biol. Rhythm. 26, 230–240 (2011).

    CAS  Google Scholar 

  273. 273.

    Asher, G. et al. Poly(ADP-ribose) polymerase 1 participates in the phase entrainment of circadian clocks to feeding. Cell 142, 943–953 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  274. 274.

    Wolff, G. & Esser, K. A. Scheduled exercise phase shifts the circadian clock in skeletal muscle. Med. Sci. Sports Exerc. 44, 1663–1670 (2012).

    PubMed  PubMed Central  Google Scholar 

  275. 275.

    Williams, J. et al. Epithelial and stromal circadian clocks are inversely regulated by their mechano-matrix environment. J. Cell. Sci. 131, jcs208223 (2018).

    PubMed  PubMed Central  Google Scholar 

  276. 276.

    Yang, N. et al. Cellular mechano-environment regulates the mammary circadian clock. Nat. Commun. 8, 14287 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  277. 277.

    Lee, J. E. & Edery, I. Circadian regulation in the ability of Drosophila to combat pathogenic infections. Curr. Biol. 18, 195–199 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  278. 278.

    Stone, E. F. et al. The circadian clock protein timeless regulates phagocytosis of bacteria in Drosophila. PLOS Pathog. 8, e1002445 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  279. 279.

    Shirasu-Hiza, M. M., Dionne, M. S., Pham, L. N., Ayres, J. S. & Schneider, D. S. Interactions between circadian rhythm and immunity in Drosophila melanogaster. Curr. Biol. 17, R353–R355 (2007).

    CAS  PubMed  Google Scholar 

  280. 280.

    Toda, H., Williams, J. A., Gulledge, M. & Sehgal, A. A sleep-inducing gene, nemuri, links sleep and immune function in Drosophila. Science 363, 509–515 (2019).

    CAS  PubMed  Google Scholar 

  281. 281.

    Xu, F. et al. Circadian clocks function in concert with heat shock organizing protein to modulate mutant huntingtin aggregation and toxicity. Cell Rep. 27, 59–70.e4 (2019).

    CAS  PubMed  Google Scholar 

  282. 282.

    Means, J. C. et al. Drosophila spaghetti and doubletime link the circadian clock and light to caspases, apoptosis and tauopathy. PLOS Genet. 11, e1005171 (2015).

    PubMed  PubMed Central  Google Scholar 

  283. 283.

    Koh, K., Evans, J. M., Hendricks, J. C. & Sehgal, A. A Drosophila model for age-associated changes in sleep:wake cycles. Proc. Natl Acad. Sci. USA 103, 13843–13847 (2006).

    CAS  PubMed  Google Scholar 

  284. 284.

    Luo, W. et al. Old flies have a robust central oscillator but weaker behavioral rhythms that can be improved by genetic and environmental manipulations. Aging Cell 11, 428–438 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  285. 285.

    Rakshit, K. & Giebultowicz, J. M. Cryptochrome restores dampened circadian rhythms and promotes healthspan in aging Drosophila. Aging Cell 12, 752–762 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  286. 286.

    Kuintzle, R. C. et al. Circadian deep sequencing reveals stress-response genes that adopt robust rhythmic expression during aging. Nat. Commun. 8, 14529 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  287. 287.

    Mattis, J. & Sehgal, A. Circadian rhythms, sleep, and disorders of aging. Trends Endocrinol. Metab. 27, 192–203 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  288. 288.

    Krishnan, N., Kretzschmar, D., Rakshit, K., Chow, E. & Giebultowicz, J. M. The circadian clock gene period extends healthspan in aging Drosoph. melanogaster. Aging 1, 937–948 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  289. 289.

    Krishnan, N. et al. Loss of circadian clock accelerates aging in neurodegeneration-prone mutants. Neurobiol. Dis. 45, 1129–1135 (2012).

    CAS  PubMed  Google Scholar 

  290. 290.

    Kondratov, R. V., Vykhovanets, O., Kondratova, A. A. & Antoch, M. P. Antioxidant N-acetyl-L-cysteine ameliorates symptoms of premature aging associated with the deficiency of the circadian protein BMAL1. Aging 1, 979–987 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  291. 291.

    Beaver, L. M. et al. Circadian regulation of glutathione levels and biosynthesis in Drosophila melanogaster. PLOS ONE 7, e50454 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  292. 292.

    Edgar, R. S. et al. Peroxiredoxins are conserved markers of circadian rhythms. Nature 485, 459–464 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  293. 293.

    Levandovski, R. et al. Depression scores associate with chronotype and social jetlag in a rural population. Chronobiol. Int. 28, 771–778 (2011).

    PubMed  Google Scholar 

  294. 294.

    Parsons, M. J. et al. Social jetlag, obesity and metabolic disorder: investigation in a cohort study. Int. J. Obes. 39, 842–848 (2015).

    CAS  Google Scholar 

  295. 295.

    Roenneberg, T., Allebrandt, K. V., Merrow, M. & Vetter, C. Social jetlag and obesity. Curr. Biol. 22, 939–943 (2012).

    CAS  PubMed  Google Scholar 

  296. 296.

    Rutters, F. et al. Is social jetlag associated with an adverse endocrine, behavioral, and cardiovascular risk profile? J. Biol. Rhythm. 29, 377–383 (2014).

    Google Scholar 

  297. 297.

    Merikanto, I. et al. Associations of chronotype and sleep with cardiovascular diseases and type 2 diabetes. Chronobiol. Int. 30, 470–477 (2013).

    PubMed  Google Scholar 

  298. 298.

    Wittmann, M., Dinich, J., Merrow, M. & Roenneberg, T. Social jetlag: misalignment of biological and social time. Chronobiol. Int. 23, 497–509 (2006).

    PubMed  Google Scholar 

  299. 299.

    Yu, J. H. et al. Evening chronotype is associated with metabolic disorders and body composition in middle-aged adults. J. Clin. Endocrinol. Metab. 100, 1494–1502 (2015).

    CAS  PubMed  Google Scholar 

  300. 300.

    Chang, A. M., Aeschbach, D., Duffy, J. F. & Czeisler, C. A. Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness. Proc. Natl Acad. Sci. USA 112, 1232–1237 (2015).

    CAS  PubMed  Google Scholar 

  301. 301.

    Chinoy, E. D., Duffy, J. F. & Czeisler, C. A. Unrestricted evening use of light-emitting tablet computers delays self-selected bedtime and disrupts circadian timing and alertness. Physiol. Rep. 6, e13692 (2018).

    PubMed  PubMed Central  Google Scholar 

  302. 302.

    Cho, H. et al. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature 485, 123–127 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  303. 303.

    Chung, S. et al. Impact of circadian nuclear receptor REV-ERBα on midbrain dopamine production and mood regulation. Cell 157, 858–868 (2014).

    CAS  PubMed  Google Scholar 

  304. 304.

    Amador, A. et al. Pharmacological and genetic modulation of REV-ERB activity and expression affects orexigenic gene expression. PLOS ONE 11, e0151014 (2016).

    PubMed  PubMed Central  Google Scholar 

  305. 305.

    Banerjee, S. et al. Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour. Nat. Commun. 5, 5759 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  306. 306.

    Solt, L. A. et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 485, 62–68 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  307. 307.

    Sulli, G. et al. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature 553, 351–355 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  308. 308.

    Griffin, P. et al. Circadian clock protein Rev-erbα regulates neuroinflammation. Proc. Natl Acad. Sci. USA 116, 5102–5107 (2019).

    CAS  PubMed  Google Scholar 

  309. 309.

    Kojetin, D., Wang, Y., Kamenecka, T. M. & Burris, T. P. Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB. ACS Chem. Biol. 6, 131–134 (2011).

    CAS  PubMed  Google Scholar 

  310. 310.

    Montaigne, D. et al. Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erbα antagonism: a single-centre propensity-matched cohort study and a randomised study. Lancet 391, 59–69 (2018).

    PubMed  Google Scholar 

  311. 311.

    He, B. et al. The small molecule Nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome. Cell Metab. 23, 610–621 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  312. 312.

    Shinozaki, A. et al. Potent effects of flavonoid Nobiletin on amplitude, period, and phase of the circadian clock rhythm in PER2::LUCIFERASE mouse embryonic fibroblasts. PLOS ONE 12, e0170904 (2017).

    PubMed  PubMed Central  Google Scholar 

  313. 313.

    Onozuka, H. et al. Nobiletin, a citrus flavonoid, improves memory impairment and Aβ pathology in a transgenic mouse model of Alzheimer’s disease. J. Pharmacol. Exp. Ther. 326, 739–744 (2008).

    CAS  PubMed  Google Scholar 

  314. 314.

    Yabuki, Y., Ohizumi, Y., Yokosuka, A., Mimaki, Y. & Fukunaga, K. Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice. Neuroscience 259, 126–141 (2014).

    CAS  PubMed  Google Scholar 

  315. 315.

    Yi, L. T. et al. Involvement of monoaminergic systems in the antidepressant-like effect of nobiletin. Physiol. Behav. 102, 1–6 (2011).

    CAS  PubMed  Google Scholar 

  316. 316.

    Humphries, P. S. et al. Carbazole-containing sulfonamides and sulfamides: discovery of cryptochrome modulators as antidiabetic agents. Bioorg. Med. Chem. Lett. 26, 757–760 (2016).

    CAS  PubMed  Google Scholar 

  317. 317.

    Chun, S. K. et al. A synthetic cryptochrome inhibitor induces anti-proliferative effects and increases chemosensitivity in human breast cancer cells. Biochem. Biophys. Res. Commun. 467, 441–446 (2015).

    CAS  PubMed  Google Scholar 

  318. 318.

    Engelmann, W. in Neuropsychiatric Disorders and Disturbances in the Circadian System of Man (ed. Halaris, A.) 263–289 (Elsevier, 1987).

  319. 319.

    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).

    CAS  PubMed  Google Scholar 

  320. 320.

    Li, J., Lu, W. Q., Beesley, S., Loudon, A. S. & Meng, Q. J. Lithium impacts on the amplitude and period of the molecular circadian clockwork. PLOS ONE 7, e33292 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  321. 321.

    Klein, P. S. & Melton, D. A. A molecular mechanism for the effect of lithium on development. Proc. Natl Acad. Sci. USA 93, 8455–8459 (1996).

    CAS  PubMed  Google Scholar 

  322. 322.

    Stambolic, V., Ruel, L. & Woodgett, J. R. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr. Biol. 6, 1664–1668 (1996).

    CAS  PubMed  Google Scholar 

  323. 323.

    Turek, F. W. Circadian clocks: not your grandfather’s clock. Science 354, 992–993 (2016).

    CAS  PubMed  Google Scholar 

  324. 324.

    Panda, S. The arrival of circadian medicine. Nat. Rev. Endocrinol. 15, 67–69 (2019).

    PubMed  Google Scholar 

  325. 325.

    Rosbash, M. The implications of multiple circadian clock origins. PLOS Biol. 7, e62 (2009).

    PubMed  Google Scholar 

  326. 326.

    Dodd, A. N. et al. Plant circadian clocks increase photosynthesis, growth, survival, and competitive advantage. Science 309, 630–633 (2005).

    CAS  PubMed  Google Scholar 

  327. 327.

    von Saint Paul, U. & Aschoff, J. Longevity among blowflies Phormia terraenovae R.D. kept in non-24-hour light–dark cycles. J. Comp Physiol. 127, 191–195 (1978).

    Google Scholar 

  328. 328.

    Klarsfeld, A. & Rouyer, F. Effects of circadian mutations and LD periodicity on the life span of Drosophila melanogaster. J. Biol. Rhythm. 13, 471–478 (1998).

    CAS  Google Scholar 

  329. 329.

    Wyse, C. A., Coogan, A. N., Selman, C., Hazlerigg, D. G. & Speakman, J. R. Association between mammalian lifespan and circadian free-running period: the circadian resonance hypothesis revisited. Biol. Lett. 6, 696–698 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  330. 330.

    Spoelstra, K., Wikelski, M., Daan, S., Loudon, A. S. & Hau, M. Natural selection against a circadian clock gene mutation in mice. Proc. Natl Acad. Sci. USA 113, 686–691 (2016).

    CAS  PubMed  Google Scholar 

  331. 331.

    Kumar, S., Kumar, D., Paranjpe, D. A., Akarsh, C.R. & Sharma, V. K. Selection on the timing of adult emergence results in altered circadian clocks in fruit flies Drosophila melanogaster. J. Exp. Biol. 210, 906–918 (2007).

    PubMed  Google Scholar 

  332. 332.

    Kumar, S., Kumar, D., Harish, V. S., Divya, S. & Sharma, V. K. Possible evidence for morning and evening oscillators in Drosophila melanogaster populations selected for early and late adult emergence. J. Insect Physiol. 53, 332–342 (2007).

    CAS  PubMed  Google Scholar 

  333. 333.

    Kannan, N. N., Vaze, K. M. & Sharma, V. K. Clock accuracy and precision evolve as a consequence of selection for adult emergence in a narrow window of time in fruit flies Drosophila melanogaster. J. Exp. Biol. 215, 3527–3534 (2012).

    PubMed  Google Scholar 

  334. 334.

    Kyriacou, C. P., Peixoto, A. A., Sandrelli, F., Costa, R. & Tauber, E. Clines in clock genes: fine-tuning circadian rhythms to the environment. Trends Genet. 24, 124–132 (2008).

    CAS  PubMed  Google Scholar 

  335. 335.

    Beauchamp, M. et al. Closely related fruit fly species living at different latitudes diverge in their circadian clock anatomy and rhythmic behavior. J. Biol. Rhythm. 33, 602–613 (2018).

    Google Scholar 

  336. 336.

    Menegazzi, P. et al. Adaptation of circadian neuronal network to photoperiod in high-latitude European Drosophilids. Curr. Biol. 27, 833–839 (2017).

    CAS  PubMed  Google Scholar 

  337. 337.

    DeCoursey, P. J. in Chronobiology: Biological Timekeeping (eds Dunlap, J. C., Loros, J. J., & DeCoursey, P. J.) 27–66 (Sinauer Associates, 2004).

  338. 338.

    Imafuku, M. & Haramura, T. Activity rhythm of Drosophila kept in complete darkness for 1300 generations. Zool. Sci. 28, 195–198 (2011).

    PubMed  Google Scholar 

  339. 339.

    Beale, A. D., Whitmore, D. & Moran, D. Life in a dark biosphere: a review of circadian physiology in “arrhythmic” environments. J. Comp. Physiol. B 186, 947–968 (2016).

    PubMed  PubMed Central  Google Scholar 

  340. 340.

    Arnold, W. et al. Circadian rhythmicity persists through the Polar night and midnight sun in Svalbard reindeer. Sci. Rep. 8, 14466 (2018).

    PubMed  PubMed Central  Google Scholar 

  341. 341.

    Uchida, Y., Hirayama, J. & Nishina, H. A common origin: signaling similarities in the regulation of the circadian clock and DNA damage responses. Biol. Pharm. Bull 33, 535–544 (2010).

    CAS  PubMed  Google Scholar 

  342. 342.

    Gehring, W. & Rosbash, M. The coevolution of blue-light photoreception and circadian rhythms. J. Mol. Evol. 57, S286–S289 (2003).

    CAS  PubMed  Google Scholar 

  343. 343.

    Eckel-Mahan, K. L. et al. Coordination of the transcriptome and metabolome by the circadian clock. Proc. Natl Acad. Sci. USA 109, 5541–5546 (2012).

    CAS  PubMed  Google Scholar 

  344. 344.

    Fustin, J. M. et al. Rhythmic nucleotide synthesis in the liver: temporal segregation of metabolites. Cell Rep. 1, 341–349 (2012).

    CAS  PubMed  Google Scholar 

  345. 345.

    Wang, G. Z. et al. Cycling transcriptional networks optimize energy utilization on a genome scale. Cell Rep. 13, 1868–1880 (2015). This paper shows that rhythmically expressed yeast genes require more energy to generate their products than non-cycling genes.

    CAS  PubMed  PubMed Central  Google Scholar 

  346. 346.

    Beaver, L. M. et al. Loss of circadian clock function decreases reproductive fitness in males of Drosophila melanogaster. Proc. Natl Acad. Sci. USA 99, 2134–2139 (2002).

    CAS  PubMed  Google Scholar 

  347. 347.

    Katewa, S. D. et al. Peripheral circadian clocks mediate dietary restriction-dependent changes in lifespan and fat metabolism in Drosophila. Cell Metab. 23, 143–154 (2016).

    CAS  PubMed  Google Scholar 

  348. 348.

    Klichko, V. I. et al. Aging alters circadian regulation of redox in Drosophila. Front. Genet. 6, 83 (2015).

    PubMed  PubMed Central  Google Scholar 

  349. 349.

    Abbott, S. M., Reid, K. J. & Zee, P. C. Circadian rhythm sleep–wake disorders. Psychiatr. Clin. North Am. 38, 805–823 (2015).

    PubMed  Google Scholar 

  350. 350.

    Huhne, A., Welsh, D. K. & Landgraf, D. Prospects for circadian treatment of mood disorders. Ann. Med. 50, 637–654 (2018).

    PubMed  Google Scholar 

  351. 351.

    Thosar, S. S., Butler, M. P. & Shea, S. A. Role of the circadian system in cardiovascular disease. J. Clin. Invest. 128, 2157–2167 (2018).

    PubMed  PubMed Central  Google Scholar 

  352. 352.

    Maury, E., Hong, H. K. & Bass, J. Circadian disruption in the pathogenesis of metabolic syndrome. Diabetes Metab. 40, 338–346 (2014).

    CAS  PubMed  Google Scholar 

  353. 353.

    Perelis, M., Ramsey, K. M., Marcheva, B. & Bass, J. Circadian transcription from β cell function to diabetes pathophysiology. J. Biol. Rhythm. 31, 323–336 (2016).

    CAS  Google Scholar 

  354. 354.

    Labrecque, N. & Cermakian, N. Circadian clocks in the immune system. J. Biol. Rhythm. 30, 277–290 (2015).

    CAS  Google Scholar 

  355. 355.

    Lamia, K. A. Ticking time bombs: connections between circadian clocks and cancer. F1000Res 6, 1910 (2017).

    PubMed  PubMed Central  Google Scholar 

  356. 356.

    Miller, B. H. & Takahashi, J. S. Central circadian control of female reproductive function. Front. Endocrinol. 4, 195 (2013).

    Google Scholar 

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Acknowledgements

This work was supported by grants from the National Institutes of Health (GM054339 and NS053087) and Calico Lifesciences LLC to M.W.Y.

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M.W.Y. established the scope of the review. A.P. and S.A. researched data and wrote the subsections on mammals and flies, respectively, and jointly contributed to the remaining subsections. All authors made substantial contributions to the discussion and revision of the manuscript prior to submission.

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Correspondence to Michael W. Young.

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Research in the laboratory of M.W.Y is partly funded by Calico Lifesciences LLC.

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Nature Reviews Molecular Cell Biology thanks Felix Naef, Satchidananda Panda and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Circadian rhythmicity

A physiological or behavioural oscillation with a period of ~24 h, which is sustained in constant conditions and entrainable by external cues such as light.

Eclosion

The emergence of an insect from the pupal case.

E/E′-box

The DNA element CACGT(T/G), which is bound by the basic helix–loop–helix transcription factors CLOCK–BMAL1.

D-box

(DBP response element). A DNA element (TTATG(C/T)AA) bound by transcription regulators of the proline and acidic amino acid-rich–basic leucine zipper family (DBP, TEF, HLF) and E4BP4 (also known as NFIL3).

Basic leucine zipper

(bZip). A protein domain common in many DNA-binding proteins.

Topologically associating domains

Genomic regions with extensive internal chromatin interactions (such as between promoters and distal enhancers) and fewer contacts with neighbouring regions.

Delayed sleep phase disorder

A circadian rhythm sleep disorder characterized by a delay in the major sleep episode relative to the desired sleep time.

Efferent projections

Axons exiting from a particular region such as the suprachiasmatic nuclei.

Prothoracic gland

An endocrine gland in certain insects regulating moulting by secretion of steroid hormones such as ecdysone.

Oenocytes

Pheromone-producing secretory cells found in most insects.

Malpighian tubules

An excretory and osmoregulatory system used by some invertebrates; Malpighian tubules are functionally similar to the mammalian kidney.

Proboscis

A flexible and tubular mouth part used by many insect species for feeding.

Short neuropeptide F

A signalling molecule released by subpopulations of neurons including some clock neurons; orthologue to mammalian neuropeptide Y.

Cistrome

The genome-wide set of cis-acting targets of a trans-acting factor, for example, the in vivo genome-wide binding locations of a transcription factor.

Ionotropic receptors

Ligand-gated ion channels, which form pores for specific ions in the plasma membrane upon binding of a specific extracellular ligand.

Chordotonal organ

A sensory organ found along the body wall of insects and crustaceans, which operates as an auditory organ, a position and movement sensor or a sensor of wind, gravity or temperature.

Parabiosis

The surgical joining of two organisms to form one shared physiological system.

Chronotype

The intrinsic preference of an individual with regards to the timing of rest and activity during a 24-h period, including early (also referred to as morningness), intermediate or late (also referred to as eveningness).

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Patke, A., Young, M.W. & Axelrod, S. Molecular mechanisms and physiological importance of circadian rhythms. Nat Rev Mol Cell Biol 21, 67–84 (2020). https://doi.org/10.1038/s41580-019-0179-2

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