Zinc Deficiency and Epigenetics

  • Harvest F. GuEmail author
  • Xiuli Zhang
Living reference work entry


Zinc (Zn) is an essential micronutrient element. This element in relation with the structure and function of many proteins and enzymes is important for a variety of biological activities, including epigenetic regulations. Zinc deficiency is common in many parts of the world and particularly in poor populations. Accumulating evidence has demonstrated that several key enzymes and zinc finger proteins with zinc atom(s) in the reactive center and binding site play important roles in DNA methylation and histone modifications. Therefore, zinc deficiency may disrupt the functions of these enzymes and proteins and result in epigenetic dysregulation. Furthermore, zinc deficiency may enhance inflammatory response and subsequently alter DNA methylation status of the genes involved in inflammation. In this chapter, we first describe zinc dietary sources and deficiency, and then discuss direct and indirect effects of zinc deficiency in DNA and chromatin methylation alteration. Finally, we prospect a new zinc biomarker and further investigation on the effects of zinc deficiency in epigenetics.


Betaine homocysteine methyltransferase DNA methylation Epigenetics Histone modification Methionine synthase Oocyte epigenetic programming Zinc Zinc deficiency Zn-dependent methyltransferases Zinc finger proteins Zinc food sources 

List of Abbreviation


adequate intake


betaine homocysteine methyltransferase


dihomo-γ-linolenic acid


thymidylate monophosphate


daily value of foods


food and agriculture organization




linoleic acid


methionine synthase


recommended dietary allowance


recommended nutrient intake


S-adenosyl methionine


solute-linked carrier


World Health Organization


zinc finger protein


  1. Ackland ML, Michalczyk AA (2016) Zinc and infant nutrition. Arch Biochem Biophys 611:51–57CrossRefPubMedGoogle Scholar
  2. Apgar J (1985) Zinc and reproduction. Annu Rev Nutr 5:43–68CrossRefPubMedGoogle Scholar
  3. Bernhardt ML, Kim AM, O’Halloran TV, Woodruff TK (2011) Zinc requirement during meiosis I-meiosis II transition in mouse oocytes is independent of the MOS-MAPK pathway. Biol Reprod. 84(3):526–36.Google Scholar
  4. Blattler A, Yao L, Wang Y, Ye Z, Jin VX, Farnham PJ (2013) ZBTB33 binds unmethylated regions of the genome associated with actively expressed genes. Epigenetics Chromatin 6(1):13CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bonaventura P, Benedetti G, Albarède F, Miossec P (2015) Zinc and its role in immunity and inflammation. Autoimmun Rev 14(4):277–285CrossRefPubMedGoogle Scholar
  6. Castro C, Millian NS, Garrow TA (2008) Liver betaine-homocysteine S-methyltransferase activity undergoes a redox switch at the active site zinc. Arch Biochem Biophys 472(1):26–33CrossRefPubMedPubMedCentralGoogle Scholar
  7. Cai Y, Li J, Yang S, Li P, Zhang X, Liu H (2012) CIBZ, a novel BTB domain containing protein, is involved in mouse spinal cord injury via mitochondrial pathway independent of p53 gene. PLoS One 7(3):e33156CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chasapis CT, Loutsidou AC, Spiliopoulou CA, Stefanidou ME (2012) Zinc and human health: an update. Arch Toxicol 86(4):521–534CrossRefPubMedGoogle Scholar
  9. Chimienti F, Devergnas S, Favier A, Seve M (2004) Identification and cloning of a beta-cell specific zinc transporter, ZnT-8, localized into insulin secretory granules. Diabetes 53(9):2330–2337CrossRefPubMedGoogle Scholar
  10. Corry GN, Tanasijevic B, Barry ER, Krueger W, Rasmussen TP (2009) Epigenetic regulatory mechanisms during preimplantation development. Birth Defects Res C Embryo Today 87(4):297–313CrossRefPubMedGoogle Scholar
  11. Debey P, Szöllösi MS, Szöllösi D, Vautier D, Girousse A, Besombes D (1993) Competent mouse oocytes isolated from antral follicles exhibit different chromatin organization and follow different maturation dynamics. Mol Reprod Dev 36(1):59–74CrossRefPubMedGoogle Scholar
  12. Dhawan DK, Chadha VD (2010) Zinc: a promising agent in dietary chemoprevention of cancer. Indian J Med Res 132:676–682PubMedPubMedCentralGoogle Scholar
  13. Dreosti IE (2001) Zinc and the gene. Mutat Res 475(1–2):161–167CrossRefPubMedGoogle Scholar
  14. Du J, Johnson LM, Jacobsen SE, Patel DJ (2015) DNA methylation pathways and their crosstalk with histone methylation. Nat Rev Mol Cell Biol 16(9):519–532CrossRefPubMedPubMedCentralGoogle Scholar
  15. Evans GW (1986) Zinc and its deficiency diseases. Clin Physiol Biochem 4(1):94–98PubMedGoogle Scholar
  16. Foster M, Samman S (2012) Zinc and regulation of inflammatory cytokines: implications for cardiometabolic disease. Nutrients 4(7):676–694CrossRefPubMedPubMedCentralGoogle Scholar
  17. Frassinetti S, Bronzetti G, Caltavuturo L, Cini M, Croce CD (2006) The role of zinc in life: a review. J Environ Pathol Toxicol Oncol 25(3):597–610CrossRefPubMedGoogle Scholar
  18. Fu Y, Tian W, Pratt EB, Dirling LB, Shyng SL, Meshul CK et al (2009) Down-regulation of ZnT8 expression in INS-1 rat pancreatic beta cells reduces insulin content and glucose-inducible insulin secretion. PLoS One 4(5):e5679CrossRefPubMedPubMedCentralGoogle Scholar
  19. Grüngreiff K, Reinhold D, Wedemeyer H (2016) The role of zinc in liver cirrhosis. Ann Hepatol 15(1):7–16CrossRefPubMedGoogle Scholar
  20. Gumulec J, Masarik M, Krizkova S, Adam V, Hubalek J, Hrabeta J, Eckschlager T, Stiborova M, Kizek R (2011) Insight to physiology and pathology of zinc(II) ions and their actions in breast and prostate carcinoma. Curr Med Chem 18(33):5041–5051CrossRefPubMedGoogle Scholar
  21. Gu HF (2015) Genetic, Epigenetic and Biological Effects of Zinc Transporter (SLC30A8) in Type 1 and Type 2 Diabetes. Curr Diabetes Rev. [Epub ahead of print] PubMed PMID: 26593983Google Scholar
  22. Gu HF (2016) Genetic, Epigenetic and Biological Effects of Zinc Transporter (SLC30A8) in Type 1 and Type 2 Diabetes. Curr Diabetes Rev 12:1–9Google Scholar
  23. Hales BF, Grenier L, Lalancette C, Robaire B (2011) Epigenetic programming: from gametes to blastocyst. Birth Defects Res A Clin Mol Teratol 91(8):652–665CrossRefPubMedGoogle Scholar
  24. Ho E (2004) Zinc deficiency, DNA damage and cancer risk. J Nutr Biochem 15(10):572–578CrossRefPubMedGoogle Scholar
  25. Institute of Medicine, Food and Nutrition Board (2001) Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. National Academy Press, Washington, DCGoogle Scholar
  26. Sandström B (1997) Bioavailability of zinc. Eur J Clin Nutr 51(1 Suppl):S17–S19PubMedGoogle Scholar
  27. Jing M, Rech L, Wu Y, Goltz D, Taylor CG, House JD (2015) Effects of zinc deficiency and zinc supplementation on homocysteine levels and related enzyme expression in rats. J Trace Elem Med Biol 30:77–82CrossRefPubMedGoogle Scholar
  28. Katsarou A, Gudbjörnsdottir S, Rawshani A, Dabelea D, Bonifacio E, Anderson BJ, Jacobsen LM, Schatz DA, Lernmark Å (2017) Type 1 diabetes mellitus. Nat Rev Dis Primers 3:17016CrossRefPubMedGoogle Scholar
  29. Kim AM, Vogt S, O’Halloran TV, Woodruff TK (2010) Zinc availability regulates exit from meiosis in maturing mammalian oocytes. Nat Chem Biol 6(9):674–681CrossRefPubMedPubMedCentralGoogle Scholar
  30. Keen CL, Hanna LA, Lanoue L, Uriu-Adams JY, Rucker RB, Clegg MS (2003) Developmental consequences of trace mineral deficiencies in rodents: acute and long-term effects. J Nutr 133(5 Suppl 1):1477S–1480SPubMedGoogle Scholar
  31. Knez M, Stangoulis JCR, Zec M, Debeljak-Martacic J, Pavlovic Z, Gurinovic M, Glibetic M (2016) An initial evaluation of newly proposed biomarker of zinc status in humans – linoleic acid: dihomo-γ-linolenic acid (LA:DGLA) ratio. Clin Nutr ESPEN 15:85–92CrossRefPubMedGoogle Scholar
  32. Lacerda LD, Molisani MM (2006) Three decades of Cd and Zn contamination in Sepetiba Bay, SE Brazil: Evidence from the mangrove oyster Crassostraea rhizophorae. Mar Pollut Bull 52(8):974–977CrossRefPubMedGoogle Scholar
  33. Laity JH, Lee BM, Wright PE (2001) Zinc finger proteins: new insights into structural and functional diversity. Curr Opin Struct Biol 11(1):39–46CrossRefPubMedGoogle Scholar
  34. Lin CC, Huang YL (2015) Chromium, zinc and magnesium status in type 1 diabetes. Curr Opin Clin Nutr Metab Care 18(6):588–592CrossRefPubMedGoogle Scholar
  35. Liuzzi JP, Cousins RJ (2004) Mammalian zinc transporters. Annu Rev Nutr 24:151–172CrossRefPubMedGoogle Scholar
  36. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ (2006) Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 367(9524):1747–1757CrossRefPubMedGoogle Scholar
  37. Maret W (2017) Zinc in Pancreatic Islet Biology, Insulin Sensitivity, and Diabetes. Prev Nutr Food Sci 22(1):1–8CrossRefPubMedPubMedCentralGoogle Scholar
  38. Matthews RG, Goulding CW (1997) Enzyme-catalyzed methyl transfers to thiols: the role of zinc. Curr Opin Chem Biol 1(3):332–339CrossRefPubMedGoogle Scholar
  39. Miao X, Sun W, Fu Y, Miao L, Cai L (2013) Zinc homeostasis in the metabolic syndrome and diabetes. Front Med 7(1):31–52CrossRefPubMedGoogle Scholar
  40. Mocchegiani E, Muzzioli M, Giacconi R (2000) Zinc and immunoresistance to infection in aging: new biological tools. Trends Pharmacol Sci 21(6):205–208CrossRefPubMedGoogle Scholar
  41. Murphy EW, Willis BW, Watt BK (1975) Provisional tables on the zinc content of foods. J Am Diet Assoc 66(4):345–355PubMedGoogle Scholar
  42. Páez-Osuna F, Ruiz-Fernández AC, Botello AV, Ponce-Vélez G, Osuna-López JI, Frías-Espericueta MG, López-López G, Zazueta-Padilla HM (2002) Concentrations of selected trace metals (Cu, Pb, Zn), organochlorines (PCBs, HCB) and total PAHs in mangrove oysters from the Pacific Coast of Mexico: an overview. Mar Pollut Bull 44(11):1303–1308CrossRefPubMedGoogle Scholar
  43. Prasad AS (2001) Discovery of human zinc deficiency: impact on human health. Nutrition 17(7–8):685–687CrossRefPubMedGoogle Scholar
  44. Prasad AS (2012) Discovery of human zinc deficiency: 50 years later. J Trace Elem Med Biol 26(2–3):66–69CrossRefPubMedGoogle Scholar
  45. Prasad AS (2013) Discovery of human zinc deficiency: its impact on human health and disease. Adv Nutr 4(2):176–190CrossRefPubMedPubMedCentralGoogle Scholar
  46. Prasad AS (2014) Zinc is an Antioxidant and Anti-Inflammatory Agent: Its Role in Human Health. Front Nutr 1:14CrossRefPubMedPubMedCentralGoogle Scholar
  47. Seman NA, Mohamud WN, Östenson CG, Brismar K, Gu HF (2015) Increased DNA methylation of the SLC30A8 gene promoter is associated with type 2 diabetes in a Malay population. Clin Epigenetics 7:30CrossRefPubMedPubMedCentralGoogle Scholar
  48. Sharif R, Thomas P, Zalewski P, Fenech M (2012) The role of zinc in genomic stability. Mutat Res 733(1–2):111–121CrossRefPubMedGoogle Scholar
  49. Shimbo T, Wade PA (2016) Proteins that read DNA methylation. Adv Exp Med Biol 945:303–320CrossRefPubMedGoogle Scholar
  50. Smith BC, Denu JM (2009) Chemical mechanisms of histone lysine and arginine modifications. Biochim Biophys Acta 1789(1):45–57CrossRefPubMedGoogle Scholar
  51. Tian X, Diaz FJ (2013) Acute dietary zinc deficiency before conception compromises oocyte epigenetic programming and disrupts embryonic development. Dev Biol 376(1):51–61CrossRefPubMedPubMedCentralGoogle Scholar
  52. Uriu-Adams JY, Keen CL (2010) Zinc and reproduction: effects of zinc deficiency on prenatal and early postnatal development. Birth Defects Res B Dev Reprod Toxicol 89(4):313–325CrossRefPubMedGoogle Scholar
  53. Wang H, Liu W, Black S, Turner O, Daniel JM, Dean-Colomb W, He QP, Davis M, Yates C (2016) Kaiso, a transcriptional repressor, promotes cell migration and invasion of prostate cancer cells through regulation of miR-31 expression. Oncotarget 7(5):5677–5689CrossRefPubMedGoogle Scholar
  54. Wessells KR, Brown KH (2012) Estimating the global prevalence of zinc deficiency: results based on zinc availability in national food supplies and the prevalence of stunting. PLoS One 7(11):e50568CrossRefPubMedPubMedCentralGoogle Scholar
  55. Wessells KR, Singh GM, Brown KH (2012) Estimating the global prevalence of inadequate zinc intake from national food balance sheets: effects of methodological assumptions. PLoS One 7(11):e50565CrossRefPubMedPubMedCentralGoogle Scholar
  56. Wilson RL, Grieger JA, Bianco-Miotto T, Roberts CT (2016) Association between Maternal Zinc Status, Dietary Zinc Intake and Pregnancy Complications: A Systematic Review. Nutrients 8(10):pii: E641CrossRefGoogle Scholar
  57. Wise A (1995) Phytate and zinc bioavailability. Int J Food Sci Nutr 46(1):53–63CrossRefPubMedGoogle Scholar
  58. Wong CP, Rinaldi NA, Ho E (2015) Zinc deficiency enhanced inflammatory response by increasing immune cell activation and inducing IL6 promoter demethylation. Mol Nutr Food Res 59(5):991–999CrossRefPubMedPubMedCentralGoogle Scholar
  59. World Health Organization and Food and Agriculture Organization of the United Nations (2004) Vitamin and mineral requirements in human nutrition, 2nd edn. World Health Organization, GenevaGoogle Scholar
  60. Wu LC (2002) ZAS: C2H2 zinc finger proteins involved in growth and development. Gene Expr 10(4):137–152CrossRefPubMedGoogle Scholar
  61. Zhang X, Liang D, Lian X, Chi ZH, Wang X, Zhao Y, Ping Z (2016b) Effect of zinc deficiency on mouse renal interstitial fibrosis in diabetic nephropathy. Mol Med Rep 14(6):5245–5252PubMedGoogle Scholar
  62. Zhang X, Liang D, Fan J, Lian X, Zhao Y, Wang X, Chi ZH, Zhang P (2016a) Zinc Attenuates Tubulointerstitial Fibrosis in Diabetic Nephropathy Via Inhibition of HIF Through PI-3K Signaling. Biol Trace Elem Res 173(2):372–383CrossRefPubMedGoogle Scholar
  63. Zhou L, Zhong Y, Yang FH, Li ZB, Zhou J, Liu XH, Li M, Hu F (2016) Kaiso represses the expression of glucocorticoid receptor via a methylation-dependent mechanism and attenuates the anti-apoptotic activity of glucocorticoids in breast cancer cells. BMB Rep 49(3):167–172CrossRefPubMedPubMedCentralGoogle Scholar
  64. Zuccotti M, Piccinelli A, Giorgi Rossi P, Garagna S, Redi CA (1995) Chromatin organization during mouse oocyte growth. Mol Reprod Dev 41(4):479–485CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Clinical Science, Intervention and TechnologyKarolinska University HospitalStockholmSweden
  2. 2.Center for Molecular Medicine, Karolinska InstituteStockholmSweden
  3. 3.Benxi Center HospitalChina Medical UniversityLiaoningChina

Personalised recommendations