Skip to main content

The Epigenetic Language of Circadian Clocks

  • Chapter
  • First Online:
Circadian Clocks

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 217))

Abstract

Epigenetic control, which includes DNA methylation and histone modifications, leads to chromatin remodeling and regulated gene expression. Remodeling of chromatin constitutes a critical interface of transducing signals, such as light or nutrient availability, and how these are interpreted by the cell to generate permissive or silenced states for transcription. CLOCK-BMAL1-mediated activation of clock-controlled genes (CCGs) is coupled to circadian changes in histone modification at their promoters. Several chromatin modifiers, such as the deacetylases SIRT1 and HDAC3 or methyltransferase MLL1, have been shown to be recruited to the promoters of the CCGs in a circadian manner. Interestingly, the central element of the core clock machinery, the transcription factor CLOCK, also possesses histone acetyltransferase activity. Rhythmic expression of the CCGs is abolished in the absence of these chromatin modifiers. Here we will discuss the evidence demonstrating that chromatin remodeling is at the crossroads of circadian rhythms and regulation of metabolism and cellular proliferation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 349.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 449.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 449.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Adamantidis A, de Lecea L (2009) The hypocretins as sensors for metabolism and arousal. J Physiol 587:33–40

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Aksoy P, White TA, Thompson M, Chini EN (2006) Regulation of intracellular levels of NAD: a novel role for CD38. Biochem Biophys Res Commun 345:1386–1392

    Article  PubMed  CAS  Google Scholar 

  • Alenghat T, Meyers K, Mullican SE, Leitner K, Adeniji-Adele A, Avila J, Bucan M, Ahima RS, Kaestner KH, Lazar MA (2008) Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 456:997–1000

    Article  PubMed  CAS  Google Scholar 

  • Antoch MP, Kondratov RV (2013) Pharmacological modulators of the circadian clock as potential therapeutic drugs: focus on genotoxic/anticancer therapy. In: Kramer A, Merrow M (eds) Circadian clocks, vol 217, Handbook of experimental pharmacology. Springer, Heidelberg

    Chapter  Google Scholar 

  • Antoch MP, Gorbacheva VY, Vykhovanets O, Toshkov IA, Kondratov RV, Kondratova AA, Lee C, Nikitin AY (2008) Disruption of the circadian clock due to the Clock mutation has discrete effects on aging and carcinogenesis. Cell Cycle 7:1197–1204

    Article  PubMed  CAS  Google Scholar 

  • Arble DM, Bass J, Laposky AD, Vitaterna MH, Turek FW (2009) Circadian timing of food intake contributes to weight gain. Obesity 17:2100–2102

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Bishop NA, Guarente L (2007) Genetic links between diet and lifespan: shared mechanisms from yeast to humans. Nat Rev Genet 8:835–844

    Article  PubMed  CAS  Google Scholar 

  • Brown SA, Azzi A (2013) Peripheral circadian oscillators in mammals. In: Kramer A, Merrow M (eds) Circadian clocks, vol 217, Handbook of experimental pharmacology. Springer, Heidelberg

    Chapter  Google Scholar 

  • Buhr ED, Takahashi JS (2013) Molecular components of the mammalian circadian clock. In: Kramer A, Merrow M (eds) Circadian clocks, vol 217, Handbook of experimental pharmacology. Springer, Heidelberg

    Chapter  Google Scholar 

  • Bunger MK, Wilsbacher LD, Moran SM, Clendenin C, Radcliffe LA, Hogenesch JB, Simon MC, Takahashi JS, Bradfield CA (2000) Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103:1009–1017

    Article  PubMed  CAS  Google Scholar 

  • Chen ST, Choo KB, Hou MF, Yeh KT, Kuo SJ, Chang JG (2005) Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis 26:1241–1246

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • De Bacquer D, Van Risseghem M, Clays E, Kittel F, De Backer G, Braeckman L (2009) Rotating shift work and the metabolic syndrome: a prospective study. Int J Epidemiol 38:848–854

    Article  PubMed  Google Scholar 

  • DiTacchio L, Le HD, Vollmers C, Hatori M, Witcher M, Secombe J, Panda S (2011) Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock. Science 333:1881–1885

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Duong HA, Robles MS, Knutti D, Weitz CJ (2011) A molecular mechanism for circadian clock negative feedback. Science 332:1436–1439

    Article  PubMed  CAS  Google Scholar 

  • Etchegaray JP, Lee C, Wade PA, Reppert SM (2003) Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421:177–182

    Article  PubMed  CAS  Google Scholar 

  • Feng D, Liu T, Sun Z, Bugge A, Mullican SE, Alenghat T, Liu XS, Lazar MA (2011) A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331: 1315–1319

    Article  PubMed  CAS  Google Scholar 

  • Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, Bhimavarapu A, Luikenhuis S, de Cabo R, Fuchs C, Hahn WC, Guarente LP, Sinclair DA (2008) The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS ONE 3:e2020

    Article  PubMed  Google Scholar 

  • Fonken LK, Workman JL, Walton JC, Weil ZM, Morris JS, Haim A, Nelson RJ (2010) Light at night increases body mass by shifting the time of food intake. Proc Natl Acad Sci USA 107: 18664–18669

    Article  PubMed  CAS  Google Scholar 

  • Fontaine C, Dubois G, Duguay Y, Helledie T, Vu-Dac N, Gervois P, Soncin F, Mandrup S, Fruchart JC, Fruchart-Najib J, Staels B (2003) The orphan nuclear receptor Rev-Erbalpha is a peroxisome proliferator-activated receptor (PPAR) gamma target gene and promotes PPARgamma-induced adipocyte differentiation. J Biol Chem 278:37672–37680

    Article  PubMed  CAS  Google Scholar 

  • Frescas D, Valenti L, Accili D (2005) Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J Biol Chem 280: 20589–20595

    Article  PubMed  CAS  Google Scholar 

  • Fu L, Pelicano H, Liu J, Huang P, Lee C (2002) The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111:41–50

    Article  PubMed  CAS  Google Scholar 

  • Gaddameedhi S, Selby CP, Kaufmann WK, Smart RC, Sancar A (2011) Control of skin cancer by the circadian rhythm. Proc Natl Acad Sci USA 108(46):18790–18795

    Article  PubMed  CAS  Google Scholar 

  • Gauger MA, Sancar A (2005) Cryptochrome, circadian cycle, cell cycle checkpoints, and cancer. Cancer Res 65:6828–6834

    Article  PubMed  CAS  Google Scholar 

  • Gery S, Gombart AF, Yi WS, Koeffler C, Hofmann WK, Koeffler HP (2005) Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia. Blood 106:2827–2836

    Article  PubMed  CAS  Google Scholar 

  • Gery S, Komatsu N, Baldjyan L, Yu A, Koo D, Koeffler HP (2006) The circadian gene per1 plays an important role in cell growth and DNA damage control in human cancer cells. Mol Cell 22: 375–382

    Article  PubMed  CAS  Google Scholar 

  • Gery S, Virk RK, Chumakov K, Yu A, Koeffler HP (2007) The clock gene Per2 links the circadian system to the estrogen receptor. Oncogene 26:7916–7920

    Article  PubMed  CAS  Google Scholar 

  • Gorbacheva VY, Kondratov RV, Zhang R, Cherukuri S, Gudkov AV, Takahashi JS, Antoch MP (2005) Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK-BMAL1 transactivation complex. Proc Natl Acad Sci USA 102:3407–3412

    Article  PubMed  CAS  Google Scholar 

  • Green KA, Carroll JS (2007) Oestrogen-receptor-mediated transcription and the influence of co-factors and chromatin state. Nat Rev Cancer 7:713–722

    Article  PubMed  CAS  Google Scholar 

  • Hirayama J, Cardone L, Doi M, Sassone-Corsi P (2005) Common pathways in circadian and cell cycle clocks: light-dependent activation of Fos/AP-1 in zebrafish controls CRY-1a and WEE-1. Proc Natl Acad Sci USA 102:10194–10199

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Hoffman AE, Zheng T, Ba Y, Zhu Y (2008) The circadian gene NPAS2, a putative tumor suppressor, is involved in DNA damage response. Mol Cancer Res 6:1461–1468

    Article  PubMed  CAS  Google Scholar 

  • Hunt T, Sassone-Corsi P (2007) Riding tandem: circadian clocks and the cell cycle. Cell 129: 461–464

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080

    Article  PubMed  CAS  Google Scholar 

  • Kang TH, Reardon JT, Kemp M, Sancar A (2009) Circadian oscillation of nucleotide excision repair in mammalian brain. Proc Natl Acad Sci USA 106(8):2864–2867

    Article  PubMed  CAS  Google Scholar 

  • Karlsson B, Knutsson A, Lindahl B (2001) Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27,485 people. Occup Environ Med 58:747–752

    Article  PubMed  CAS  Google Scholar 

  • Katada S, Sassone-Corsi P (2010) The histone methyltransferase MLL1 permits the oscillation of circadian gene expression. Nat Struct Mol Biol 17:1414–1421

    Article  PubMed  CAS  Google Scholar 

  • Katada S, Imhof A, Sassone-Corsi P (2012) Common threads: metabolism and epigenetics. Cell 148:24–28

    Article  PubMed  CAS  Google Scholar 

  • Klevecz RR, Shymko RM, Blumenfeld D, Braly PS (1987) Circadian gating of S phase in human ovarian cancer. Cancer Res 47:6267–6271

    PubMed  CAS  Google Scholar 

  • Kobayashi M, Wood PA, Hrushesky WJ (2002) Circadian chemotherapy for gynecological and genitourinary cancers. Chronobiol Int 19:237–251

    Article  PubMed  CAS  Google Scholar 

  • Kohsaka A, Laposky AD, Ramsey KM, Estrada C, Joshu C, Kobayashi Y, Turek FW, Bass J (2007) High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab 6:414–421

    Article  PubMed  CAS  Google Scholar 

  • Lamia KA, Storch KF, Weitz CJ (2008) Physiological significance of a peripheral tissue circadian clock. Proc Natl Acad Sci USA 105:15172–15177

    Article  PubMed  CAS  Google Scholar 

  • Levi F, Focan C, Karaboue A, de la Valette V, Focan-Henrard D, Baron B, Kreutz F, Giacchetti S (2007) Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Adv Drug Deliv Rev 59:1015–1035

    Article  PubMed  CAS  Google Scholar 

  • Li X, Zhang S, Blander G, Tse JG, Krieger M, Guarente L (2007) SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol Cell 28:91–106

    Article  PubMed  Google Scholar 

  • Lis CG, Grutsch JF, Wood P, You M, Rich I, Hrushesky WJ (2003) Circadian timing in cancer treatment: the biological foundation for an integrative approach. Integr Cancer Ther 2:105–111

    Article  PubMed  CAS  Google Scholar 

  • Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, Ko CH, Ivanova G, Omura C, Mo S, Vitaterna MH, Lopez JP, Philipson LH, Bradfield CA, Crosby SD, JeBailey L, Wang X, Takahashi JS, Bass J (2010) Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466:627–631

    Article  PubMed  CAS  Google Scholar 

  • Marcheva B, Ramsey KM, Peek CB, Affinati A, Maury E, Bass J (2013) Circadian clocks and metabolism. In: Kramer A, Merrow M (eds) Circadian clocks, vol 217, Handbook of experimental pharmacology. Springer, Heidelberg

    Chapter  Google Scholar 

  • Masri S, Sassone-Corsi P (2010) Plasticity and specificity of the circadian epigenome. Nat Neurosci 13:1324–1329

    Article  PubMed  CAS  Google Scholar 

  • Matsuo T, Yamaguchi S, Mitsui S, Emi A, Shimoda F, Okamura H (2003) Control mechanism of the circadian clock for timing of cell division in vivo. Science 302:255–259

    Article  PubMed  CAS  Google Scholar 

  • Merrow M, Spoelstra K, Roenneberg T (2005) The circadian cycle: daily rhythms from behaviour to genes. EMBO Rep 6:930–935

    Article  PubMed  CAS  Google Scholar 

  • Miller BH, McDearmon EL, Panda S, Hayes KR, Zhang J, Andrews JL, Antoch MP, Walker JR, Esser KA, Hogenesch JB, Takahashi JS (2007) Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation. Proc Natl Acad Sci USA 104:3342–3347

    Article  PubMed  CAS  Google Scholar 

  • Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, Guarente LP, Sassone-Corsi P (2008) The NAD+−dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134:329–340

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Ortiz-Tudela E, Mteyrek A, Ballesta A, Innominato PF, Lévi F (2013) Cancer chronotherapeutics: experimental, theoretical and clinical aspects. In: Kramer A, Merrow M (eds) Circadian clocks, vol 217, Handbook of experimental pharmacology. Springer, Heidelberg

    Chapter  Google Scholar 

  • Ozturk N, Lee JH, Gaddameedhi S, Sancar A (2009) Loss of cryptochrome reduces cancer risk in p53 mutant mice. Proc Natl Acad Sci USA 106(8):2841–2846

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U (2002) The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110:251–260

    Article  PubMed  CAS  Google Scholar 

  • Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, Marcheva B, Hong HK, Chong JL, Buhr ED, Lee C, Takahashi JS, Imai S, Bass J (2009) Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324:651–654

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Rudic RD, McNamara P, Curtis AM, Boston RC, Panda S, Hogenesch JB, Fitzgerald GA (2004) BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol 2:e377

    Article  PubMed  Google Scholar 

  • Ruthenburg AJ, Li H, Patel DJ, Allis CD (2007) Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 8:983–994

    Article  PubMed  CAS  Google Scholar 

  • Sadacca LA, Lamia KA, deLemos AS, Blum B, Weitz CJ (2011) An intrinsic circadian clock of the pancreas is required for normal insulin release and glucose homeostasis in mice. Diabetologia 54:120–124

    Article  PubMed  CAS  Google Scholar 

  • Sahar S, Sassone-Corsi P (2007) Circadian clock and breast cancer: a molecular link. Cell Cycle 6: 1329–1331

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Sahar S, Sassone-Corsi P (2012) Regulation of metabolism: the circadian clock dictates the time. Trends Endocrinol Metab 23:1–8

    Article  PubMed  CAS  Google Scholar 

  • 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. doi:100368 [pii]

    PubMed  Google Scholar 

  • Saper CB, Chou TC, Elmquist JK (2002) The need to feed: homeostatic and hedonic control of eating. Neuron 36:199–211

    Article  PubMed  CAS  Google Scholar 

  • Schibler U, Sassone-Corsi P (2002) A web of circadian pacemakers. Cell 111:919–922

    Article  PubMed  CAS  Google Scholar 

  • Schwer B, Verdin E (2008) Conserved metabolic regulatory functions of sirtuins. Cell Metab 7: 104–112

    Article  PubMed  CAS  Google Scholar 

  • Slat E, Freeman GM, Herzog ED (2013) The clock in the brain: neurons, glia and networks in daily rhythms. In: Kramer A, Merrow M (eds) Circadian clocks, vol 217, Handbook of experimental pharmacology. Springer, Heidelberg

    Chapter  Google Scholar 

  • Smaaland R, Lote K, Sothern RB, Laerum OD (1993) DNA synthesis and ploidy in non-Hodgkin’s lymphomas demonstrate intrapatient variation depending on circadian stage of cell sampling. Cancer Res 53:3129–3138

    PubMed  CAS  Google Scholar 

  • Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, Bass J (2005) Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308:1043–1045

    Article  PubMed  CAS  Google Scholar 

  • Unsal-Kacmaz K, Mullen TE, Kaufmann WK, Sancar A (2005) Coupling of human circadian and cell cycles by the timeless protein. Mol Cell Biol 25:3109–3116

    Article  PubMed  Google Scholar 

  • Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, Guarente L, Weinberg RA (2001) hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107:149–159

    Article  PubMed  CAS  Google Scholar 

  • Yang WS, Stockwell BR (2008) Inhibition of casein kinase 1-epsilon induces cancer-cell-selective, PERIOD2-dependent growth arrest. Genome Biol 9:R92

    Article  PubMed  Google Scholar 

  • Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413:131–138

    Article  PubMed  CAS  Google Scholar 

  • Zuber AM, Centeno G, Pradervand S, Nikolaeva S, Maquelin L, Cardinaux L, Bonny O, Firsov D (2009) Molecular clock is involved in predictive circadian adjustment of renal function. Proc Natl Acad Sci USA 106:16523–16528

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paolo Sassone-Corsi .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Sahar, S., Sassone-Corsi, P. (2013). The Epigenetic Language of Circadian Clocks. In: Kramer, A., Merrow, M. (eds) Circadian Clocks. Handbook of Experimental Pharmacology, vol 217. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-25950-0_2

Download citation

Publish with us

Policies and ethics