The Epigenetically Modulated Circadian System: Implications for Nutrition and Health. Nutritional Modulation of the Circadian Epigenome

  • Lidia DaimielEmail author
Reference work entry


The biological clock is a complex puzzle of molecular pieces that must work coordinately to ensure a proper cellular function. The circadian epigenome is the most recently discovered set of clock molecular pieces. It involves DNA methylation, histone acetylation/deacetylation, histone methylation/demethylation, and noncoding RNAs. These epigenomic modifications related to the circadian system add complexity to this process. In this regard, the circadian system is similar to the solar system with the CLOCK/BMAL1 heterodimer in the center and the other molecular and epigenomic components of the circadian system orbiting around it. The particular characteristic of the epigenome is that it is modifiable and environmental factors can affect it. Diet is one of the most important environmental factors affecting human health. We must bear in mind that diet is the only environmental factor to which we are exposed along our lives several times every day. We are even exposed to the diet of our mothers before birth. This is important because mother feeding animal studies have shown that mother diet affect circadian-related histone modifications. Diet also modifies circadian-related microRNAs. Here, we described each level of the circadian epigenome and give an insight of how diet modifies each one of them.


Circadian system Epigenome Histone acetylation/deacetylation Histone methylation/demethylation DNA methylation MicroRNAs Noncoding RNAs Chronodisruption Metabolic disorders Cardiovascular disease Nutrition 

List of Abbreviations


Clock-controlled genes


Cardiovascular disease


Histone 3


High-fat diet




Large intergenic noncoding RNAs




Metabolic syndrome


Prader-Willi syndrome


Suprachiasmatic nucleus


Small nucleolar RNAs


Type 2 diabetes mellitus



Servier Medical Art images have been used in the figures included in this manuscript. These images can be used under Creative Commons Attribution 3.0 Unported License.


  1. Aagaard-Tillery KM, Grove K, Bishop J, Ke X, Fu Q, Mcknight R, Lane RH (2008) Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome. J Mol Endocrinol 41:91–102CrossRefGoogle Scholar
  2. 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 134:317–328CrossRefGoogle Scholar
  3. Azzi A, Dallmann R, Casserly A, Rehrauer H, Patrignani A, Maier B, Kramer A, Brown SA (2014) Circadian behavior is light-reprogrammed by plastic DNA methylation. Nat Neurosci 17:377–382CrossRefGoogle Scholar
  4. Barres R, Zierath JR (2016) The role of diet and exercise in the transgenerational epigenetic landscape of T2DM. Nat Rev Endocrinol 12:441–451CrossRefGoogle Scholar
  5. Bass J, Takahashi JS (2010) Circadian integration of metabolism and energetics. Science 330:1349–1354CrossRefGoogle Scholar
  6. Belden WJ, Lewis ZA, Selker EU, Loros JJ, Dunlap JC (2011) CHD1 remodels chromatin and influences transient DNA methylation at the clock gene frequency. PLoS Genet 7:e1002166CrossRefGoogle Scholar
  7. Bonmati-Carrion MA, Arguelles-Prieto R, Martinez-Madrid MJ, Reiter R, Hardeland R, Rol MA, Madrid JA (2014) Protecting the melatonin rhythm through circadian healthy light exposure. Int J Mol Sci 15:23448–23500CrossRefGoogle Scholar
  8. Borengasser SJ, Kang P, Faske J, Gomez-Acevedo H, Blackburn ML, Badger TM, Shankar K (2014) High fat diet and in utero exposure to maternal obesity disrupts circadian rhythm and leads to metabolic programming of liver in rat offspring. PLoS One 9:e84209CrossRefGoogle Scholar
  9. Coon SL, Munson PJ, Cherukuri PF, Sugden D, Rath MF, Moller M, Clokie SJ, Fu C, Olanich ME, Rangel Z, Werner T, Mullikin JC, Klein DC (2012) Circadian changes in long noncoding RNAs in the pineal gland. Proc Natl Acad Sci USA 109:13319–13324CrossRefGoogle Scholar
  10. Corbalan-Tutau MD, Gomez-Abellan P, Madrid JA, Canteras M, Ordovas JM, Garaulet M (2015) Toward a chronobiological characterization of obesity and metabolic syndrome in clinical practice. Clin Nutr 34:477–483CrossRefGoogle Scholar
  11. Crosio C, Cermakian N, Allis CD, Sassone-Corsi P (2000) Light induces chromatin modification in cells of the mammalian circadian clock. Nat Neurosci 3:1241–1247CrossRefGoogle Scholar
  12. Chartoumpekis DV, Zaravinos A, Ziros PG, Iskrenova RP, Psyrogiannis AI, Kyriazopoulou VE, Habeos IG (2012) Differential expression of micrornas in adipose tissue after long-term high-fat diet-induced obesity in mice. PLoS One 7:e34872CrossRefGoogle Scholar
  13. Chen L, Yang G (2015) Recent advances in circadian rhythms in cardiovascular system. Front Pharmacol 6:71PubMedPubMedCentralGoogle Scholar
  14. Chen R, D'alessandro M, Lee C (2013) miRNAs are required for generating a time delay critical for the circadian oscillator. Curr Biol 23:1959–1968CrossRefGoogle Scholar
  15. 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 26:1241–1246CrossRefGoogle Scholar
  16. Cheng HY, Papp JW, Varlamova O, Dziema H, Russell B, Curfman JP, Nakazawa T, Shimizu K, Okamura H, Impey S, Obrietan K (2007) MicroRNA modulation of circadian-clock period and entrainment. Neuron 54:813–829CrossRefGoogle Scholar
  17. Daimiel-Ruiz L, Klett-Mingo M, Konstantinidou V, Mico V, Aranda JF, Garcia B, Martinez-Botas J, Davalos A, Fernandez-Hernando C, Ordovas JM (2015) Dietary lipids modulate the expression of miR-107, an miRNA that regulates the circadian system. Mol Nutr Food Res 59:552–565CrossRefGoogle Scholar
  18. Doi M, Hirayama J, Sassone-Corsi P (2006) Circadian regulator CLOCK is a histone acetyltransferase. Cell 125:497–508CrossRefGoogle Scholar
  19. Du NH, Arpat AB, De Matos M, Gatfield D (2014) MicroRNAs shape circadian hepatic gene expression on a transcriptome-wide scale. Elife 3:e02510CrossRefGoogle Scholar
  20. Duong HA, Weitz CJ (2014) Temporal orchestration of repressive chromatin modifiers by circadian clock period complexes. Nat Struct Mol Biol 21:126–132CrossRefGoogle Scholar
  21. Etchegaray JP, Lee C, Wade PA, Reppert SM (2003) Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421:177–182CrossRefGoogle Scholar
  22. 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 281:21209–21215CrossRefGoogle Scholar
  23. Feillet C, Van Der Horst GT, Levi F, Rand DA, Delaunay F (2015) Coupling between the circadian clock and cell cycle oscillators: implication for healthy cells and malignant growth. Front Neurol 6:96CrossRefGoogle Scholar
  24. Fernandez-Hernando C, Ramirez CM, Goedeke L, Suarez Y (2013) MicroRNAs in metabolic disease. Arterioscler Thromb Vasc Biol 33:178–185CrossRefGoogle Scholar
  25. Ferrell JM, Chiang JY (2015) Circadian rhythms in liver metabolism and disease. Acta Pharm Sin B 5:113–122CrossRefGoogle Scholar
  26. Figueredo Dde S, Gitai DL, Andrade TG (2015) Daily variations in the expression of miR-16 and miR-181a in human leukocytes. Blood Cells Mol Dis 54:364–368CrossRefGoogle Scholar
  27. Garaulet M, Ordovás JM (2012) Chronobiology and obesity. Springer, New York/Heidelberg/Dordrecht/LondonGoogle Scholar
  28. Gavrilas LI, Ionescu C, Tudoran O, Lisencu C, Balacescu O, Miere D (2016) The role of bioactive dietary components in modulating miRNA expression in colorectal cancer. Nutrients 8(10). pii. E590Google Scholar
  29. Gil-Zamorano J, Martin R, Daimiel L, Richardson K, Giordano E, Nicod N, Garcia-Carrasco B, Soares SM, Iglesias-Gutierrez E, Lasuncion MA, Sala-Vila A, Ros E, Ordovas JM, Visioli F, Davalos A (2014) Docosahexaenoic acid modulates the enterocyte Caco-2 cell expression of microRNAs involved in lipid metabolism. J Nutr 144:575–585CrossRefGoogle Scholar
  30. 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 450:1086–1090CrossRefGoogle Scholar
  31. Joska TM, Zaman R, Belden WJ (2014) Regulated DNA methylation and the circadian clock: implications in cancer. Biology (Basel) 3:560–577Google Scholar
  32. Katada S, Sassone-Corsi P (2010) The histone methyltransferase MLL1 permits the oscillation of circadian gene expression. Nat Struct Mol Biol 17:1414–1421CrossRefGoogle Scholar
  33. Lee KH, Kim SH, Lee HR, Kim W, Kim DY, Shin JC, Yoo SH, Kim KT (2013) MicroRNA-185 oscillation controls circadian amplitude of mouse Cryptochrome 1 via translational regulation. Mol Biol Cell 24:2248–2255CrossRefGoogle Scholar
  34. Lim AS, Srivastava GP, Yu L, Chibnik LB, Xu J, Buchman AS, Schneider JA, Myers AJ, Bennett DA, De Jager PL (2014) 24-hour rhythms of DNA methylation and their relation with rhythms of RNA expression in the human dorsolateral prefrontal cortex. PLoS Genet 10:e1004792CrossRefGoogle Scholar
  35. Marques-Rocha JL, Milagro FI, Mansego ML, Zulet MA, Bressan J, Martinez JA (2016) Expression of inflammation-related miRNAs in white blood cells from subjects with metabolic syndrome after 8 wk of following a Mediterranean diet-based weight loss program. Nutrition 32:48–55CrossRefGoogle Scholar
  36. Masri S, Sassone-Corsi P (2010) Plasticity and specificity of the circadian epigenome. Nat Neurosci 13:1324–1329CrossRefGoogle Scholar
  37. Mico V, Diez-Ricote L, Daimiel L (2016) Nutrigenetics and nutrimiromics of the circadian system: the time for human health. Int J Mol Sci 17Google Scholar
  38. Miki T, Matsumoto T, Zhao Z, Lee CC (2013) p53 regulates period2 expression and the circadian clock. Nat Commun 4:2444CrossRefGoogle Scholar
  39. Mukherji A, Kobiita A, Damara M, Misra N, Meziane H, Champy MF, Chambon P (2015) 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–E6698CrossRefGoogle Scholar
  40. Na YJ, Sung JH, Lee SC, Lee YJ, Choi YJ, Park WY, Shin HS, Kim JH (2009) Comprehensive analysis of microRNA-mRNA co-expression in circadian rhythm. Exp Mol Med 41:638–647CrossRefGoogle Scholar
  41. 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 134:329–340CrossRefGoogle Scholar
  42. Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone-Corsi P (2009) Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science 324:654–657CrossRefGoogle Scholar
  43. Nam HJ, Boo K, Kim D, Han DH, Choe HK, Kim CR, Sun W, Kim H, Kim K, Lee H, Metzger E, Schuele R, Yoo SH, Takahashi JS, Cho S, Son GH, Baek SH (2014) Phosphorylation of LSD1 by PKCalpha is crucial for circadian rhythmicity and phase resetting. Mol Cell 53:791–805CrossRefGoogle Scholar
  44. Oosterman JE, Kalsbeek A, La Fleur SE, Belsham DD (2015) Impact of nutrients on circadian rhythmicity. Am J Physiol Regul Integr Comp Physiol 308:R337–R350CrossRefGoogle Scholar
  45. Powell WT, Coulson RL, Crary FK, Wong SS, Ach RA, Tsang P, Alice Yamada N, Yasui DH, Lasalle JM (2013) A Prader-Willi locus lncRNA cloud modulates diurnal genes and energy expenditure. Hum Mol Genet 22:4318–4328CrossRefGoogle Scholar
  46. Powell WT, Lasalle JM (2015) Epigenetic mechanisms in diurnal cycles of metabolism and neurodevelopment. Hum Mol Genet 24:R1–R9CrossRefGoogle Scholar
  47. 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 324:651–654CrossRefGoogle Scholar
  48. Saud SM, Li W, Morris NL, Matter MS, Colburn NH, Kim YS, Young MR (2014) Resveratrol prevents tumorigenesis in mouse model of Kras activated sporadic colorectal cancer by suppressing oncogenic Kras expression. Carcinogenesis 35:2778–2786CrossRefGoogle Scholar
  49. Shen H, He H, Li J, Chen W, Wang X, Guo L, Peng Z, He G, Zhong S, Qi Y, Terzaghi W, Deng XW (2012) Genome-wide analysis of DNA methylation and gene expression changes in two Arabidopsis ecotypes and their reciprocal hybrids. Plant Cell 24:875–892CrossRefGoogle Scholar
  50. Shende VR, Goldrick MM, Ramani S, Earnest DJ (2011) Expression and rhythmic modulation of circulating microRNAs targeting the clock gene Bmal1 in mice. PLoS One 6:e22586CrossRefGoogle Scholar
  51. Shende VR, Kim SM, Neuendorff N, Earnest DJ (2014) MicroRNAs function as cis-and trans-acting modulators of peripheral circadian clocks. FEBS Lett 588:3015–3022CrossRefGoogle Scholar
  52. Shih MC, Yeh KT, Tang KP, Chen JC, Chang JG (2006) Promoter methylation in circadian genes of endometrial cancers detected by methylation-specific PCR. Mol Carcinog 45:732–740CrossRefGoogle Scholar
  53. Singh NP, Singh UP, Rouse M, Zhang J, Chatterjee S, Nagarkatti PS, Nagarkatti M (2016) Dietary indoles suppress delayed-type hypersensitivity by inducing a switch from proinflammatory Th17 cells to anti-inflammatory regulatory T cells through regulation of microRNA. J Immunol 196:1108–1122CrossRefGoogle Scholar
  54. Suelves M, Carrio E, Nunez-Alvarez Y, Peinado MA (2016) DNA methylation dynamics in cellular commitment and differentiation. Brief Funct Genomics. 15(6):443–453Google Scholar
  55. Suter M, Bocock P, Showalter L, Hu M, Shope C, Mcknight R, Grove K, Lane R, Aagaard-Tillery K (2011) Epigenomics: maternal high-fat diet exposure in utero disrupts peripheral circadian gene expression in nonhuman primates. Faseb J 25:714–726CrossRefGoogle Scholar
  56. Suter MA, Takahashi D, Grove KL, Aagaard KM (2013) Postweaning exposure to a high-fat diet is associated with alterations to the hepatic histone code in Japanese macaques. Pediatr Res 74:252–258CrossRefGoogle Scholar
  57. Tan X, Zhang P, Zhou L, Yin B, Pan H, Peng X (2012) Clock-controlled mir-142-3p can target its activator, Bmal1. BMC Mol Biol 13:27CrossRefGoogle Scholar
  58. Taniguchi H, Fernandez AF, Setien F, Ropero S, Ballestar E, Villanueva A, Yamamoto H, Imai K, Shinomura Y, Esteller M (2009) Epigenetic inactivation of the circadian clock gene BMAL1 in hematologic malignancies. Cancer Res 69:8447–8454CrossRefGoogle Scholar
  59. Vollmers C, Schmitz RJ, Nathanson J, Yeo G, Ecker JR, Panda S (2012) Circadian oscillations of protein-coding and regulatory RNAs in a highly dynamic mammalian liver epigenome. Cell Metab 16:833–845CrossRefGoogle Scholar
  60. Wang XC, Zhan XR, Li XY, Yu JJ, Liu XM (2014) MicroRNA-185 regulates expression of lipid metabolism genes and improves insulin sensitivity in mice with non-alcoholic fatty liver disease. World J Gastroenterol 20:17914–17923CrossRefGoogle Scholar
  61. Xia L, Ma S, Zhang Y, Wang T, Zhou M, Wang Z, Zhang J (2015) Daily variation in global and local DNA methylation in mouse livers. PLoS One 10:e0118101CrossRefGoogle Scholar
  62. Xu S, Witmer PD, Lumayag S, Kovacs B, Valle D (2007) MicroRNA (miRNA) transcriptome of mouse retina and identification of a sensory organ-specific miRNA cluster. J Biol Chem 282:25053–25066CrossRefGoogle Scholar
  63. Yang MY, Chang JG, Lin PM, Tang KP, Chen YH, Lin HY, Liu TC, Hsiao HH, Liu YC, Lin SF (2006) Downregulation of circadian clock genes in chronic myeloid leukemia: alternative methylation pattern of hPER3. Cancer Sci 97:1298–1307CrossRefGoogle Scholar
  64. Yang WM, Jeong HJ, Park SY, Lee W (2014) Induction of miR-29a by saturated fatty acids impairs insulin signaling and glucose uptake through translational repression of IRS-1 in myocytes. FEBS Lett 588:2170–2176CrossRefGoogle Scholar
  65. Zampetaki A, Willeit P, Drozdov I, Kiechl S, Mayr M (2012) Profiling of circulating microRNAs: from single biomarkers to re-wired networks. Cardiovasc Res 93:555–562CrossRefGoogle Scholar
  66. Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB (2014) A circadian gene expression atlas in mammals: implications for biology and medicine. Proc Natl Acad Sci USA 111:16219–16224CrossRefGoogle Scholar
  67. Zhu Y, Stevens RG, Hoffman AE, Tjonneland A, Vogel UB, Zheng T, Hansen J (2011) Epigenetic impact of long-term shiftwork: pilot evidence from circadian genes and whole-genome methylation analysis. Chronobiol Int 28:852–861CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Nutritional Genomics of the Cardiovascular Disease and ObesityFoundation IMDEA Food CEI UAM + CSICMadridSpain
  2. 2.Department of Nutrition and Bromatology, Facultad de FarmaciaUniversidad San Pablo-CEU, CEU universitiesBoadilla del Monte, MadridSpain

Personalised recommendations