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SIRT7 couples light-driven body temperature cues to hepatic circadian phase coherence and gluconeogenesis

Nature Metabolism volume 1, pages 1141–1156 (2019)Cite this article

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Abstract

The central pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) synchronizes peripheral oscillators to coordinate physiological and behavioural activities throughout the body. How circadian phase coherence between the SCN and the periphery is controlled is not well understood. Here, we identify hepatic SIRT7 as an early responsive element to light that ensures circadian phase coherence in the mouse liver. The SCN-driven body temperature (BT) oscillation induces rhythmic expression of HSP70, which promotes SIRT7 ubiquitination and proteasomal degradation. Acute temperature challenge dampens the BT oscillation and causes an advanced liver circadian phase. Further, hepatic SIRT7 deacetylates CRY1, promotes its FBXL3-mediated degradation and regulates the hepatic clock and glucose homeostasis. Loss of Sirt7 in mice leads to an advanced liver circadian phase and rapid entrainment of the hepatic clock upon daytime-restricted feeding. These data identify a BT–HSP70–SIRT7–CRY1 axis that couples the mouse hepatic clock to the central pacemaker and ensures circadian phase coherence and glucose homeostasis.

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Fig. 1: A light-entrained BT oscillation induces SIRT7 rhythmicity in mouse liver.
Fig. 2: HSP70 mediates SIRT7 degradation via the ubiquitin–proteasome pathway.
Fig. 3: SIRT7 interacts with and deacetylates CRY1.
Fig. 4: SIRT7-mediated deacetylation destabilizes CRY1.
Fig. 5: SIRT7 regulates the circadian phase in mouse livers.
Fig. 6: Expression of clock components at different AT conditions.
Fig. 7: SIRT7 counteracts phase shifting of hepatic clocks induced by RF.
Fig. 8: Sirt7 deficiency leads to impaired hepatic gluconeogenesis.
Fig. 9: SIRT7 ensures phase coherence between the central and peripheral clocks and maintains glucose homeostasis.

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Data availability

The authors declare that all of the data supporting the findings of this study are available from the corresponding authors upon reasonable request. Source Data are available online for Figs. 1–8, Extended Data Figs. 1–10 and Supplementary Figs. 2, 3 and 5–8.

References

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Panda, S. Circadian physiology of metabolism. Science 354, 1008–1015 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Reick, M., Garcia, J. A., Dudley, C. & McKnight, S. L. NPAS2: an analog of clock operative in the mammalian forebrain. Science 293, 506–509 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  6. 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).

    Article  CAS  PubMed  Google Scholar 

  7. Bunger, M. K. et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103, 1009–1017 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gekakis, N. et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 280, 1564–1569 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Takahashi, J. S., Hong, H. K., Ko, C. H. & McDearmon, E. L. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat. Rev. Genet. 9, 764–775 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dibner, C., Schibler, U. & Albrecht, U. The mammalian circadian timing system: Organization and coordination of central and peripheral clocks. Annu. Rev. Physiol. 72, 517–549 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Mohawk, J. A., Green, C. B. & Takahashi, J. S. Central and peripheral circadian clocks in mammals. Annu. Rev. Neurosci. 35, 445–462 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gerhart-Hines, Z. et al. The nuclear receptor Rev-erb alpha controls circadian thermogenic plasticity. Nature 503, 410–413 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fonken, L. K. et al. Light at night increases body mass by shifting the time of food intake. Proc. Natl Acad. Sci. USA 107, 18664–18669 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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).

    Article  CAS  PubMed  Google Scholar 

  22. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Masri, S. et al. Partitioning circadian transcription by SIRT6 leads to segregated control of cellular metabolism. Cell 158, 659–672 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li, L. et al. SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability. Nat. Commun. 7, 12235 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Barber, M. F. et al. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 487, 114–118 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Vazquez, B. N. et al. SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair. EMBO J 35, 1488–1503 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dubrovsky, Y. V., Samsa, W. E. & Kondratov, R. V. Deficiency of circadian protein CLOCK reduces lifespan and increases age-related cataract development in mice. Aging (Albany NY) 2, 936–944 (2010).

    Article  CAS  Google Scholar 

  30. Turek, F. W. et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308, 1043–1045 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kondratov, R. V., Kondratova, A. A., Gorbacheva, V. Y., Vykhovanets, O. V. & Antoch, M. P. Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock. Genes Dev. 20, 1868–1873 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kornmann, B., Schaad, O., Bujard, H., Takahashi, J. S. & Schibler, U. System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biol. 5, e34 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Koronowski, K. B. et al. Defining the independence of the liver circadian clock. Cell 177, 1448–1462.e1414 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Saini, C. et al. Real-time recording of circadian liver gene expression in freely moving mice reveals the phase-setting behavior of hepatocyte clocks. Genes Dev. 27, 1526–1536 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13, 225–238 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fischer, A. W. et al. Leptin raises defended body temperature without activating thermogenesis. Cell Rep. 14, 1621–1631 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Balchin, D., Hayer-Hartl, M. & Hartl, F. U. In vivo aspects of protein folding and quality control. Science 353, aac4354 (2016).

    Article  PubMed  CAS  Google Scholar 

  38. Kiran, S., Anwar, T., Kiran, M. & Ramakrishna, G. Sirtuin 7 in cell proliferation, stress and disease: rise of the Seventh Sirtuin! Cell Signal 27, 673–682 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Li, H. et al. Regulation of NF-kappaB activity by competition between RelA acetylation and ubiquitination. Oncogene 31, 611–623 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mukherji, A., Kobiita, A. & Chambon, P. Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours. Proc. Natl Acad. Sci. USA 112, E6683–E6690 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Lamia, K. A. et al. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 480, 552–556 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang, E. E. et al. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nat. Med. 16, 1152–1156 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yoshizawa, T. et al. SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway. Cell Metab. 19, 712–721 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Huard, J. et al. The route of administration is a major determinant of the transduction efficiency of rat-tissues by adenoviral recombinants. Gene Ther. 2, 107–115 (1995).

    CAS  PubMed  Google Scholar 

  49. Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Le Minh, N., Damiola, F., Tronche, F., Schutz, G. & Schibler, U. Glucocorticoid hormones inhibit food-induced phase-shifting of peripheral circadian oscillators. EMBO J. 20, 7128–7136 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  52. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mukherji, A. et al. Shifting eating to the circadian rest phase misaligns the peripheral clocks with the master SCN clock and leads to a metabolic syndrome. Proc. Natl Acad. Sci. USA 112, E6691–E6698 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Shi, G. et al. Dual roles of FBXL3 in the mammalian circadian feedback loops are important for period determination and robustness of the clock. Proc. Natl Acad. Sci. USA 110, 4750–4755 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Czarna, A. et al. Structures of drosophila cryptochrome and mouse cryptochrome1 provide insight into circadian function. Cell 153, 1394–1405 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Tamanini, F., Chaves, I., Bajek, M. I. & van der Horst, G. T. J. Structure function analysis of mammalian cryptochromes. Cold Spring Harb. Symp. Quant. Biol. 72, 133–139 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chaves, I. et al. Functional evolution of the photolyase/cryptochrome protein family: importance of the C terminus of mammalian CRY1 for circadian core oscillator performance. Mol. Cell. Biol. 26, 1743–1753 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Feillet, C. A. et al. Lack of food anticipation in Per2 mutant mice. Curr. Biol. 16, 2016–2022 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Liu, S. et al. Involvement of the suprachiasmatic nucleus in body temperature modulation by food deprivation in rats. Brain Res. 929, 26–36 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Lopez, M. et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat. Med. 16, 1001–1008 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kim, K. W. et al. Steroidogenic factor 1 directs programs regulating diet-induced thermogenesis and leptin action in the ventral medial hypothalamic nucleus. Proc. Natl Acad. Sci. USA 108, 10673–10678 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Martinez de Morentin, P. B. et al. Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK. Cell Metab. 20, 41–53 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Arble, D. M., Bass, J., Laposky, A. D., Vitaterna, M. H. & Turek, F. W. Circadian timing of food intake contributes to weight gain. Obes. (Silver Spring) 17, 2100–2102 (2009).

    Article  Google Scholar 

  66. Toledo, M. et al. Autophagy regulates the liver clock and glucose metabolism by degrading CRY1. Cell Metab. 28, 268–281.e264 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chen, S. F. et al. Repression of RNA polymerase I upon stress is caused by inhibition of RNA-dependent deacetylation of PAF53 by SIRT7. Mol. Cell 52, 303–313 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Ford, E. et al. Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev. 20, 1075–1080 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ryu, D. et al. A SIRT7-dependent acetylation switch of GABP beta 1 controls mitochondrial function. Cell Metab. 20, 856–869 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Fang, J. et al. Sirt7 promotes adipogenesis in the mouse by inhibiting autocatalytic activation of Sirt1. Proc. Natl Acad. Sci. USA 114, E8352–E8361 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Gubin, D. G., Gubin, G. D., Waterhouse, J. & Weinert, D. The circadian body temperature rhythm in the elderly: effect of single daily melatonin dosing. Chronobiol. Int. 23, 639–658 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Gubin, D. G. et al. Disrupted circadian rhythms of body temperature, heart rate and fasting blood glucose in prediabetes and type 2 diabetes mellitus. Chronobiol. Int. 34, 1136–1148 (2017).

    Article  CAS  PubMed  Google Scholar 

  73. Liu, B. et al. Genomic instability in laminopathy-based premature aging. Nat. Med. 11, 780–785 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Ran, F. A. et al. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 8, 2281–2308 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yan, W. W. et al. Arginine methylation of SIRT7 couples glucose sensing with mitochondria biogenesis. EMBO Rep. 19, e46377 (2018).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (grant nos. 81571374, 91849208, 81871114 and 81601215), National Key R&D Program of China (grant no. 2017YFA0503900), Science and Technology Program of Guangdong Province (grant nos. 2014A030308011, 2015A030308007 and 2017B030301016), Shenzhen Municipal Commission of Science and Technology Innovation (grant nos. JCYJ20160226191451487, KQJSCX20180328093403969, JCYJ20180507182044945 and JCYJ20160520170240403; Discipline Construction Funding of Shenzhen 2016-1452). The authors are grateful to J. Tamanini (Shenzhen University and ETediting) for editing the manuscript prior to submission.

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Author notes

  1. These authors contributed equally: Zuojun Liu, Minxian Qian.

Authors and Affiliations

  1. Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China

    Zuojun Liu, Minxian Qian, Xiaolong Tang, Jie Sun, Cheng Xu, Bing Tan, Zimei Wang & Baohua Liu

  2. National Engineering Research Center for Biotechnology (Shenzhen), Carson International Cancer Center, Medical Research Center, Shenzhen University Health Science Center, Shenzhen, China

    Zuojun Liu, Minxian Qian, Xiaolong Tang, Wenjing Hu, Shimin Sun, Shuju Zhang, Fanbiao Meng, Xinyue Cao, Jie Sun, Cheng Xu, Bing Tan & Baohua Liu

  3. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shenzhen University Health Science Center, Shenzhen, China

    Zuojun Liu, Minxian Qian, Xiaolong Tang, Shuju Zhang, Fanbiao Meng, Xinyue Cao, Jie Sun, Cheng Xu, Bing Tan, Zimei Wang & Baohua Liu

  4. Anti-aging and Regenerative Medicine Research Institution, School of Life Sciences, Shandong University of Technology, Zibo, China

    Wenjing Hu, Shimin Sun, Qiuxiang Pang & Bosheng Zhao

  5. Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China

    Guo Li

  6. Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China

    Youfei Guan

  7. Department of Renal Medicine, University College London, London, UK

    Xiongzhong Ruan

  8. Centre for Lipid Research and Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China

    Xiongzhong Ruan

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Contributions

Z.L. and M.Q. planned the experiments under guidance of B.L., performed biochemical, cellular and in vivo experiments and analyzed data. X.T., S.Z., F.M. and X.C. generated cell lines and plasmids used in this study. W.H., S.S., G.L., C.X., J.S. and B.T. did in vivo experiments. B.L. designed and supervised this study. Z.L., M.Q., Q.P., B.Z., Z.W., Y.G., X.R. and B.L. prepared and revised the manuscript.

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Correspondence to Baohua Liu.

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Extended data

Extended Data Fig. 1 Clock gene expression.

(a) Quantitative real time PCR (qRT-PCR) analysis of Sirt7, Bmal1 and Cry1 in mouse livers at the indicated circadian times. n = 3 per time point. (b) qRT-PCR analysis of Sirt7 expression in wild-type (WT) hypothalamus and livers. n = 3 per time point. (c) Representative immunoblots showing SIRT7 protein levels in WT hypothalamus (repeated three times with similar results). (d) qRT-PCR analysis of clock genes in WT liver tissues of mice maintained under normal feeding or no food (NF) from ZT0 conditions with or without a 2-h light exposure (L). n = 3 per time point. Data represent the means ± s.e.m. of three independent experiments.

Source data

Extended Data Fig. 2 Light-entrained body temperature oscillation induces SIRT7 rhythmicity in mouse liver.

(a) Measurements of mouse rectal temperature during a light/dark (LD) or dark/dark (DD) cycle. n = 6 per time point per group. (b) Measurements of mouse rectal temperature in wild-type (WT) mice at ZT16. F, feeding; F+L, feeding plus light exposure; NF, no food available; and NF+L, no food available plus light exposure. n = 6 per time point, unpaired two-tailed Student’s t test. (c) Measurements of mouse rectal temperature in WT mice fasted from ZT0 to ZT16. n = 6 per time point per group, unpaired two-tailed Student’s t test. (d) Representative immunoblots showing SIRT7 and p-AKT in fasted or refed mice. n = 4 per group. (e) Measurements of mouse rectal temperature in WT mice fasted for 24 hr (food withdraw before light-off). n = 6 per time point per group, unpaired two-tailed Student’s t test. (f) Measurements of mouse rectal temperature in fasted or refed mice. Mice were fasted for 24 hr (food withdraw before light-off) and refed (food available before light-off). n = 6 per time point per group. (g) qRT-PCR analysis of heat shock protein genes in livers of mice maintained under room or high ambient temperature. n = 3 per time point, unpaired two-tailed Student’s t test. (h) qRT-PCR analysis of Hsp70 expression in mouse livers at ZT16. n = 3 per time point, unpaired two-tailed Student’s t test. (i) qRT-PCR analysis of Hsp70 expression in WT and Sirt7 knockout (KO) mice livers at ZT16 with or without light exposure (n = 3 mice per genotype per time point), unpaired two-tailed Student’s t test. (j) Representative immunoblots showing HSP70 protein levels in WT and Sirt7 KO mice liver at ZT16 with or without light exposure (repeated three times with similar results). Data represent the means ± s.e.m. of three independent experiments.

Source data

Extended Data Fig. 3 Body temperature regulates SIRT7 levels via HSP70.

(a) Representative immunoblots showing SIRT7, HSP70 and CRY1 protein levels in wild-type (WT) and Sirt7 KO liver tissues under room or high ambient temperatures at ZT4 and ZT16. n = 3 mice per genotype per time point. (b) Measurements of mice rectal temperatures when maintained under room or high ambient temperatures at ZT4 and ZT16. n = 6 mice per genotype per time point, unpaired two-tailed Student’s t test. (c) Representative immunoblots showing SIRT7, HSP70 and CRY1 protein levels in WT and Sirt7 KO mice liver tissues when maintained under room or cold ambient temperature at ZT16. n = 3 mice per genotype per time point. (d) Measurements of mice rectal temperatures when maintained under room or cold ambient temperatures at ZT16. n = 6 mice per genotype per time point, unpaired two-tailed Student’s t test. Data represent the means ± s.e.m. of three independent experiments.

Source data

Extended Data Fig. 4 Deacetylation of CRY1 but not CRY2 by Sirtuins.

(a) Acetylation levels of FLAG-CRY1 and FLAG-CRY2 in HEK293 cells in the absence or presence of 10 mM NAM (repeated three times with similar results). (b) Acetylation levels of HA-CRY1 in the presence of over-expressed FLAG-SIRT1, FLAG-SIRT6 and FLAG-SIRT7 in HEK293 cells (repeated three times with similar results).

Source data

Extended Data Fig. 5 Acetylation levels of CRY1 lysine/arginine (K/R) mutants.

Acetylation of FLAG-CRY1 and FLAG-CRY1-2KR in the absence or presence of 10 mM NAM (repeated three times with similar results).

Source data

Extended Data Fig. 6 Clock mRNA and protein levels in unsynchronized cells.

(a,b) qRT-PCR analysis of mRNA levels of clock genes in two Sirt7 KO HEK293 cell lines (KO1 and KO2), unpaired two-tailed Student’s t test. (c) Representative immunoblots showing the protein levels of clock genes in Sirt7-KO HEK293 cells (repeated three times with similar results). (d) Representative immunoblots showing the protein levels of clock genes in cells over-expressing SIRT7 (repeated three times with similar results). (e,f) Quantification of CRY1 and BMAL1 protein levels in (c,d), unpaired two-tailed Student’s t test. Data represent the means ± s.e.m. of three independent experiments.

Source data

Extended Data Fig. 7 Protein degradation of CRY1.

(a) Representative immunoblots showing the protein levels of endogenous CRY1 in Sirt7 knockout (KO) HEK293 cells treated with 50 μg/ml CHX and/or 20 μM MG132 (b) Representative immunoblots showing protein levels of CRY1 in HEK293 cells with ectopic SIRT7 or empty vector. (c,d) Quantification of CRY1 degradation assay in (a,b), unpaired two-tailed Student’s t test. (e) Representative immunoblots showing degradation of FLAG-CRY1 and FLAG-CRY1-2KR mutants in the presence or absence of over-expressed HA-SIRT7 H187Y in HEK293 cells (repeated three times with similar results). Data represent the means ± s.e.m. of three independent experiments.

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Extended Data Fig. 8 SIRT7 regulates endogenous circadian clocks.

(a) qRT-PCR analysis of core clock genes in synchronized wild-type (WT) and Sirt7-/- mouse embryonic fibroblasts (MEFs). MEFs were synchronized by 50% horse serum, and total mRNA and protein were extracted at 4-h intervals. (b) CRY1 and BMAL1 protein levels in synchronized WT and Sirt7-/- MEFs. Representative immunoblots are shown. (c) Quantification of CRY1 and BMAL1 protein levels in (b). Data represent the means ± s.e.m. of three independent experiments. Two-way ANOVA followed by Bonferroni’s multiple comparisons test.

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Extended Data Fig. 9 Circadian gene expression in WT and Sirt7-/- hypothalamus.

(a) qRT-PCR analysis of Bmal1, Cry1, Dbp and Per2 expression in wild-type (WT) and Sirt7 knockout (KO) hypothalamus. (b) Representative immunoblots showing expression of CRY1 in WT and Sirt7-KO hypothalamus. n = 3 mice per genotype per time point. Data represent the means ± s.e.m. of three independent experiments.

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Extended Data Fig. 10 Expression of clock components at different AT acclimated for one week.

(a) Measurements of mouse rectal temperature at different AT. n = 6 mice per time point. (b) Representative immunoblots showing CRY1 SIRT7 and HSP70 protein levels at different AT. n = 3 mice per time point. (c) Quantification of band intensity in (b). (d) Real-time PCR analysis of mRNA levels of core clock genes at different AT. n = 3 mice per time point. (e) The activity profiles of mice under different AT across a circadian LD cycle. n = 6 mice per time point. (f) The activity profiles of mice under different AT in DD cycle. n = 6 mice per time point. Data represent the means ± s.e.m. of three independent experiments. Two-way ANOVA followed by Bonferroni’s multiple comparisons test. Room: 22˚C, High: 32˚C, Cold: 4˚C. Purple P, Room vs High; blue P, Room vs Cold.

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Liu, Z., Qian, M., Tang, X. et al. SIRT7 couples light-driven body temperature cues to hepatic circadian phase coherence and gluconeogenesis. Nat Metab 1, 1141–1156 (2019). https://doi.org/10.1038/s42255-019-0136-6

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