CONCLUSION

Evidence accumulating in the past few years depicts a scenario of increasing functional and molecular connections among cellular metabolism, circadian clock, and epigenetic control. The conceptual significance of these findings relates to how cells interpret the environment, by modifying their genomic response and possibly establishing a “memory” of recurrent nutritional and environmental cues. In this context, it is the chromatin landscape that most likely functions as molecular substrate of where to “write” or “erase” specific marks by posttranslational modifications of DNA and/or histones (Borrelli et al. 2008). Thus, we hypothesize that the chromatin remodelers (“writers” and “erasers” of posttranslational modifications) specifically implicated in circadian control of the genome play a central role in translating changes in cellular metabolism into epigenetic regulation. As described in this chapter, CLOCK and SIRT1 appear to occupy a central position as circadian regulators of protein acetylation (Masri and Sassone-Corsi 2010). The recent finding that the histone H3-K4 methyltransferase MLL1 controls the chromatin recruitment to circadian promoters of the CLOCK–BMAL1 complex extended the reasoning to histone methylation (Katada and Sassone-Corsi 2010). Indeed, MLL1 associates with CLOCK–BMAL1 only at specific circadian times, dictating their circadian function on CCGs. It would be highly interesting to unravel whether changes in the intracellular levels of S-adenosyl methionine, a major source of methyl groups for methyltransferases, could determine whether MLL1 circadian function can be linked to the changing levels of a metabolite. In this sense, variable availability of S-adenosyl methionine, could function as NAD+, linking the metabolite to gene expression, through the modulation of an epigenetic regulator. In our view, the circadian transcriptome and proteome are oscillating in concert, and in a coherent manner with the metabolome, in a system where the circadian machinery occupies a central place, providing the tempo for synchronicity.

ACKNOWLEDGMENTS

We thank all of the members of the laboratory for help, discussions, and fun. Our research is supported by the National Institute of Health, the Institut National de la Sante et de la Recherche Medicale (France), and Sirtris/GlaxoSmithKline.

REFERENCES

Akhtar RA, Reddy AB, Maywood ES, Clayton JD, King VM, Smith AG, Gant TW, Hastings MH, Kyriacou CP. 2002. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr Biol 12: 540–550.
Andrews NC, Faller DV. 1991. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucl Acids Res 19: 2499.
Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C, Kreppel F, Mostoslavsky R, Alt FW, Schibler U. 2008. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134: 317–328.
Bechtold DA, Gibbs JE, Loudon AS. 2010. Circadian dysfunction in disease. Trends Pharmacol Sci 31: 191–198.
Bellet MM, Sassone-Corsi P. 2010. Mammalian circadian clock and metabolism—The epigenetic link. J Cell Sci 123: 3837–3848.
Bell-Pedersen D, Cassone VM, Earnest DJ, Golden SS, Hardin PE, Thomas TL, Zoran MJ. 2005. Circadian rhythms from multiple oscillators: Lessons from diverse organisms. Nat Rev Genet 6: 544–556.
Berger SL. 2007. The complex language of chromatin regulation during transcription. Nature 447: 407–412.
Bordone L, Guarente L. 2005. Calorie restriction, SIRT1 and metabolism: Understanding longevity. Nat Rev Mol Cell Biol 4: 298–305.
Borrelli E, Nestler EJ, Allis CD, Sassone-Corsi P. 2008. Decoding the epigenetic language of neuronal plasticity. Neuron 60: 961–974.
Canto C, Jiang LQ, Deshmukh AS, Mataki C, Coste A, Lagouge M, Zierath JR, Auwerx J. 2010. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 11: 213–219.
Cermakian N, Sassone-Corsi P. 2000. Multilevel regulation of the circadian clock. Nat Rev Mol Cell Biol 1: 59–67.
Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM. 1997. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90: 569–580.
Cheung P, Tanner KG, Cheung WL, Sassone-Corsi P, Denu JM, Allis CD. 2000. Synergistic coupling of histone H3 phosphorylation and acetylation in response to epidermal growth factor stimulation. Mol Cell 5: 905–915.
Crosio C, Cermakian N, Allis CD, Sassone-Corsi P. 2000. Light induces chromatin modification in cells of the mammalian circadian clock. Nat Neurosci 3: 1241–1247.
Curtis A, Seo SB, Westgate EJ, Rudic RD, Smyth EM, Chakravarti D, FitzGerald GA, McNamara P. 2004. Histone acetyltransferase-dependent chromatin remodeling and the vascular clock. J Biol Chem 279: 7091–7097.
Czarna A, Breitkreuz H, Mahrenholz CC, Arens J, Strauss HM, Wolf E. 2011. Quantitative analyses of cryptochrome–mBMAL1 interactions: Mechanistic insights into the transcriptional regulation of the mammalian circadian clock. J Biol Chem 286: 22414–22425.
Doi M, Hirayama J, Sassone-Corsi P. 2006. Circadian regulator CLOCK is a histone acetyltransferase. Cell 125: 497–508.
Duffield GE, Best JD, Meurers BH, Bittner A, Loros JJ, Dunlap JC. 2002. Circadian programs of transcriptional activation, signaling, and protein turnover revealed by microarray analysis of mammalian cells. Curr Biol 12: 551–557.
Eckel-Mahan K, Sassone-Corsi P. 2009. Metabolism control by the circadian clock and vice versa. Nat Struct Mol Biol 16: 462–467.
Etchegaray JP, Lee C, Wade PA, Reppert SM. 2003. Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421: 177–182.
Etchegaray JP, Yang X, DeBruyne JP, Peters AH, Weaver DR, Jenuwein T, Reppert SM. 2006. The polycomb group protein EZH2 is required for mammalian circadian clock function. J Biol Chem 281: 21209–21215.
Giebultowicz JM, Stanewsky R, Hall JC, Hege DM. 2000. Transplanted Drosophila excretory tubules maintain circadian clock cycling out of phase with the host. Curr Biol 10: 107–110.
Glozak MA, Sengupta N, Zhang X, Seto E. 2005. Acetylation and deacetylation of non-histone proteins. Gene 363: 15–23.
Gorski K, Carneiro M, Schibler U. 1986. Tissue-specific in vitro transcription from the mouse albumin promoter. Cell 47: 767–776.
Hirayama J, Sahar S, Grimaldi B, Tamaru T, Takamatsu K, Nakahata Y, Sassone-Corsi P. 2007. CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature 450: 1086–1090.
Hogenesch JB, Ueda HR. 2011. Understanding systems-level properties: Timely stories from the study of clock. Nat Rev Genet 12: 407–416.
Hughes ME, DiTacchio L, Hayes KR, Vollmers C, Pulivarthy S, Baggs JE, Panda S, Hogenesch JB. 2009. Harmonics of circadian gene transcription in mammals. PLoS Genet 5: e1000442.
Imai S, Armstrong CM, Kaeberlein M, Guarente L. 2000. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403: 795–800.
Katada S, Sassone-Corsi P. 2010. The histone methyltransferase MLL1 permits the oscillation of circadian gene expression. Nat Struct Mol Biol 17: 1417–1421.
Lamia KA, Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG, Egan DF, Vasquez DS, Juguilon H, Panda S, Shaw RJ, et al. 2009. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326: 437–440.
Le Minh N, Damiola F, Tronche F, Schutz G, Schibler U. 2001. Glucocorticoid hormones inhibit food-induced phase-shifting of peripheral circadian oscillators. EMBO J 20: 7128–7136.
Lo WS, Trievel RC, Rojas JR, Duggan L, Hsu JY, Allis CD, Marmorstein R, Berger SL. 2000. Phosphorylation of serine 10 in histone H3 is functionally linked in vitro and in vivo to Gcn5-mediated acetylation at lysine 14. Mol Cell 5: 917–926.
Masri S, Sassone-Corsi P. 2010. Plasticity and specificity of the circadian epigenome. Nat Neurosci 13: 1324–1329.
Nader N, Chrousos GP, Kino T. 2009. Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: Potential physiological implications. FASEB J 23: 1572–1583.
Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, Guarente L, Sassone-Corsi P. 2008. The NAD+ dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134: 329–340.
Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone-Corsi P. 2009. Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science 324: 654–657.
Naruse Y, Oh-hashi K, Iijima N, Naruse M, Yoshioka H, Tanaka M. 2004. Circadian and light-induced transcription of clock gene Per1 depends on histone acetylation and deacetylation. Mol Cell Biol 24: 6278–6287.
Panda S, Antoch MP, Miller BH, Su AI, Schook AB, Straume M, Schultz PG, Kay SA, Takahashi JS, Hogenesch JB. 2002. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109: 307–320.
Preitner N, Brown S, Ripperger J, Le-Minh N, Damiola F, Schibler U. 2003. Orphan nuclear receptors, molecular clockwork, and the entrainment of peripheral oscillators. Novartis Found Symp 253: 89–99; discussion 99–109.
Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, Marcheva B, Hong HK, Chong JL, Buhr ED, Lee C, et al. 2009. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324: 651–654.
Reppert SM, Weaver DR. 2001. Molecular analysis of mammalian circadian rhythms. Annu Rev Physiol 63: 647–676.
Ripperger JA, Schibler U. 2006. Rhythmic CLOCK–BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nat Genet 38: 369–374.
Rutter J, Reick M, McKnight SL. 2002. Metabolism and the control of circadian rhythms. Annu Rev Biochem 71: 307–331.
Sahar S, Sassone-Corsi P. 2009. Metabolism and cancer: The circadian clock connection. Nat Rev Cancer 9: 886–896.
Sahar S, Nin V, Barbosa MT, Chini EN, Sassone-Corsi P. 2011. Altered behavioral and metabolic circadian rhythms in mice with disrupted NAD+ oscillation. Aging 3: 794–802.
Sauve AA, Wolberger C, Schramm VL, Boeke JD. 2006. The biochemistry of sirtuins. Annu Rev Biochem 75: 435–465.
Schibler U, Sassone-Corsi P. 2002. A web of circadian pacemakers. Cell 111: 919–922.
Stokkan KA, Yamazaki S, Tei H, Sakaki Y, Menaker M. 2001. Entrainment of the circadian clock in the liver by feeding. Science 291: 490–493.
Whitmore D, Foulkes NS, Strähle U, Sassone-Corsi P. 1998. Zebrafish Clock rhythmic expression reveals independent peripheral circadian oscillators. Nat Neurosci 1: 701–707.
Yan J, Wang H, Liu Y, Shao C. 2008. Analysis of gene regulatory networks in the mammalian circadian rhythm. PLoS Comput Biol 4: e1000193.
Yang XJ, Seto E. 2008. The Rpd3/Hda1 family of lysine deacetylases: From bacteria and yeast to mice and men. Nat Rev Mol Cell Biol 9: 206–218.
Young MW, Kay SA. 2001. Time zones: A comparative genetics of circadian clocks. Nat Rev Genet 2: 702–715.
Zhang EE, Liu AC, Hirota T, Miraglia LJ, Welch G, Pongsawakul PY, Liu X, Atwood A, Huss JW, Janes J, et al. 2009. A genome-wide RNAi screen for modifiers of the circadian clock in human cells. Cell 139: 199–210.
Zocchi L, Sassone-Corsi P. 2010. Joining the dots: From chromatin remodeling to neuronal plasticity. Curr Opin Neurobiol 20: 432–440.