Folate: Could We Live Without It? A Novel Epigenetic Connection

  • Catherine A. Powell
  • Gabriella Villa
  • Trevor Holmes
  • Mahua Choudhury
Living reference work entry


Folate is an essential nutrient obtained through diet and supplements. The term folate is used interchangeably with folic acid, its synthetic form. Folate is metabolized in the one-carbon pathway, and its metabolites are used for a number of biological processes. Metabolites of folate are used in nucleotide synthesis and methylation. In fact, the one-carbon pathway produces the major methyl donor used in methylation, S-adenosylmethionine (SAM). Folate and DNA methylation are, therefore, closely entwined. Folate deficiency is associated with a number of diseases including congenital disabilities. In the last couple of decades, folate or folic acid supplementation is highly promoted in pregnancy because folate deficiency leads to neural tube defects with a wide range of consequences in children. Folate deficiency is also associated with gastric and colorectal cancers, cardiovascular disease, and liver disease. Alterations in global DNA methylation and disease-specific gene methylation patterns are implicated in the development and progression of these diseases. Folate is an important nutrient to understand the epigenetic regulation of disease.


Folate DNA methylation Epigenetics Diabetes Cancer Folic acid DNA methyltransferase DNMT Cardiovascular disease Methyl donor 

List of Abbreviations


Centers for Disease Control


CpG island methylator phenotype

CpG Island

Cytosine–phosphate–Guanine Island


Cardiovascular disease


Dihydrofolate reductase


Deoxyribonucleic acid


DNA methyltransferase


Deoxythymidine monophosphate


Deoxythymidine triphosphate


Deoxyuridine monophosphate


Deoxyuridine triphosphate




Methylenetetrahydrofolate reductase


Para-aminobenzoic acid




Ten–eleven translocation proteins




World Health Organization



The Morris L. Lichtenstein Jr. Medical Research Foundation supports Mahua Choudhury.


  1. Bailey LB, Gregory JF III (1999) Folate metabolism and requirements. J Nutr 129(4):779–782PubMedGoogle Scholar
  2. Bardhan K, Liu K (2013) Epigenetics and colorectal cancer pathogenesis. Cancer 5(2):676–713CrossRefGoogle Scholar
  3. Beaudin AE, Stover PJ (2007) Folate-mediated one-carbon metabolism and neural tube defects: balancing genome synthesis and gene expression. Birth Defects Res C Embryo Today 81(3):183–203CrossRefPubMedGoogle Scholar
  4. Blom HJ, Smulders Y (2011) Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis 34(1):75–81CrossRefPubMedGoogle Scholar
  5. Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G et al (1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci USA 94(7):3290–3295CrossRefPubMedPubMedCentralGoogle Scholar
  6. Castro R, Rivera I, Struys EA, Jansen EE, Ravasco P, Camilo ME et al (2003) Increased homocysteine and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease. Clin Chem 49(8):1292–1296CrossRefPubMedGoogle Scholar
  7. CDC (2016) Folic acid (webpage, updated 28 Dec 2016).
  8. Chen W, Gao N, Shen Y, Cen JN (2010) Hypermethylation downregulates Runx3 gene expression and its restoration suppresses gastric epithelial cell growth by inducing p27 and caspase3 in human gastric cancer. J Gastroenterol Hepatol 25(4):823–831CrossRefPubMedGoogle Scholar
  9. Choi SW, Friso S (2010) Epigenetics: a new bridge between nutrition and health. Adv Nutr 1(1):8–16CrossRefPubMedPubMedCentralGoogle Scholar
  10. Clark SJ, Melki J (2002) DNA methylation and gene silencing in cancer: which is the guilty party? Oncogene 21(35):5380–5387CrossRefPubMedGoogle Scholar
  11. Cordero AM, Crider KS, Rogers LM, Cannon MJ, Berry RJ (2015) Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects: World Health Organization guidelines. MMWR Morb Mortal Wkly Rep 64(15):421–423PubMedGoogle Scholar
  12. Crider KS, Bailey LB, Berry RJ (2011) Folic acid food fortification – its history, effect, concerns, and future directions. Nutrients 3(3):370–384CrossRefPubMedPubMedCentralGoogle Scholar
  13. Crider KS, Yang TP, Berry RJ, Bailey LB (2012) Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate’s role. Adv Nutr 3(1):21–38CrossRefPubMedPubMedCentralGoogle Scholar
  14. Duthie SJ (1999) Folic acid deficiency and cancer: mechanisms of DNA instability. Br Med Bull 55(3):578–592CrossRefPubMedGoogle Scholar
  15. Ehrlich M (2002) DNA methylation in cancer: too much, but also too little. Oncogene 21(35):5400–5413CrossRefPubMedGoogle Scholar
  16. Esteller M (2002) CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 21(35):5427–5440CrossRefPubMedGoogle Scholar
  17. Gao S, Ding LH, Wang JW, Li CB, Wang ZY (2013) Diet folate, DNA methylation and polymorphisms in methylenetetrahydrofolate reductase in association with the susceptibility to gastric cancer. Asian Pac J Cancer Prev 14(1):299–302CrossRefPubMedGoogle Scholar
  18. Giovannucci E, Rimm EB, Ascherio A, Stampfer MJ, Colditz GA, Willett WC (1995) Alcohol, low-methionine – low-folate diets, and risk of colon cancer in men. J Natl Cancer Inst 87(4):265–273CrossRefPubMedGoogle Scholar
  19. Iacobazzi V, Infantino V, Castegna A, Andria G (2014) Hyperhomocysteinemia: related genetic diseases and congenital defects, abnormal DNA methylation and newborn screening issues. Mol Genet Metab 113(1–2):27–33CrossRefPubMedGoogle Scholar
  20. Irwin RE, Pentieva K, Cassidy T, Lees-Murdock DJ, McLaughlin M, Prasad G et al (2016) The interplay between DNA methylation, folate and neurocognitive development. Epigenomics 8(6):863–879CrossRefPubMedGoogle Scholar
  21. Kalnina Z, Meistere I, Kikuste I, Tolmanis I, Zayakin P, Line A (2015) Emerging blood-based biomarkers for detection of gastric cancer. World J Gastroenterol 21(41):11636–11653CrossRefPubMedPubMedCentralGoogle Scholar
  22. Kandi V, Vadakedath S (2015) Effect of DNA methylation in various diseases and the probable protective role of nutrition: a mini-review. Cureus 7(8):e309PubMedPubMedCentralGoogle Scholar
  23. Kato I, Dnistrian AM, Schwartz M, Toniolo P, Koenig K, Shore RE et al (1999) Serum folate, homocysteine and colorectal cancer risk in women: a nested case–control study. Br J Cancer 79(11–12):1917–1922CrossRefPubMedPubMedCentralGoogle Scholar
  24. Kim YI (2004) Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer? Cancer Epidemiol Biomark Prev 13(4):511–519Google Scholar
  25. Kim TY, Lee HJ, Hwang KS, Lee M, Kim JW, Bang YJ et al (2004) Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma. Lab Investig 84(4):479–484CrossRefPubMedGoogle Scholar
  26. Kruman II, Fowler AK (2014) Impaired one carbon metabolism and DNA methylation in alcohol toxicity. J Neurochem 129(5):770–780CrossRefPubMedGoogle Scholar
  27. Lee TY, Chiang EP, Shih YT, Lane HY, Lin JT, Wu CY (2014) Lower serum folate is associated with development and invasiveness of gastric cancer. World J Gastroenterol 20(32):11313–11320CrossRefPubMedPubMedCentralGoogle Scholar
  28. Li Y, Huang T, Zheng Y, Muka T, Troup J, Hu FB (2016) Folic acid supplementation and the risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. J Am Heart Assoc 5(8):e003768CrossRefPubMedPubMedCentralGoogle Scholar
  29. Liew SC (2016) Folic acid and diseases – supplement it or not? Rev Assoc Med Bras 62(1):90–100CrossRefPubMedGoogle Scholar
  30. Lindzon G, O’Connor DL (2007) Folate during reproduction: the Canadian experience with folic acid fortification. Nutr Res Pract 1(3):163–174CrossRefPubMedPubMedCentralGoogle Scholar
  31. Mattson MP, Kruman II, Duan W (2002) Folic acid and homocysteine in age-related disease. Ageing Res Rev 1(1):95–111CrossRefPubMedGoogle Scholar
  32. Medici V, Halsted CH (2013) Folate, alcohol, and liver disease. Mol Nutr Food Res 57(4):596–606CrossRefPubMedGoogle Scholar
  33. Messerschmidt DM, Knowles BB, Solter D (2014) DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos. Genes Dev 28(8):812–828CrossRefPubMedPubMedCentralGoogle Scholar
  34. Nakamura J, Tanaka T, Kitajima Y, Noshiro H, Miyazaki K (2014) Methylation-mediated gene silencing as biomarkers of gastric cancer: a review. World J Gastroenterol 20(34):11991–12006CrossRefPubMedPubMedCentralGoogle Scholar
  35. Niculescu MD, Zeisel SH (2002) Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr 132(Suppl 8):2333S–2335SPubMedGoogle Scholar
  36. NIH (2016) Folate: dietary supplement fact sheet 2016.
  37. Pacchierotti F, Spano M (2015) Environmental impact on DNA methylation in the germline: state of the art and gaps of knowledge. Biomed Res Int 2015:123484CrossRefPubMedPubMedCentralGoogle Scholar
  38. Pasechnikov V, Chukov S, Fedorov E, Kikuste I, Leja M (2014) Gastric cancer: prevention, screening and early diagnosis. World J Gastroenterol 20(38):13842–13862CrossRefPubMedPubMedCentralGoogle Scholar
  39. Pitkin RM (2007) Folate and neural tube defects. Am J Clin Nutr 85(1):285S–288SPubMedGoogle Scholar
  40. Pufulete M, Al-Ghnaniem R, Leather AJ, Appleby P, Gout S, Terry C et al (2003) Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study. Gastroenterology 124(5):1240–1248CrossRefPubMedGoogle Scholar
  41. Qu Y, Dang S, Hou P (2013) Gene methylation in gastric cancer. Clin Chim Acta 424:53–65CrossRefPubMedGoogle Scholar
  42. Quintero-Ronderos P, Montoya-Ortiz G (2012) Epigenetics and autoimmune diseases. Autoimmune Dis 2012:593720PubMedPubMedCentralGoogle Scholar
  43. Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6(8):597–610CrossRefPubMedGoogle Scholar
  44. Rosenquist TH (2013) Folate, homocysteine and the cardiac neural crest. Dev Dyn 242(3):201–218CrossRefPubMedGoogle Scholar
  45. Scaglione F, Panzavolta G (2014) Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica 44(5):480–488CrossRefPubMedGoogle Scholar
  46. Shorter KR, Felder MR, Vrana PB (2015) Consequences of dietary methyl donor supplements: is more always better? Prog Biophys Mol Biol 118(1–2):14–20CrossRefPubMedGoogle Scholar
  47. Smith ZD, Meissner A (2013) DNA methylation: roles in mammalian development. Nat Rev Genet 14(3):204–220CrossRefPubMedGoogle Scholar
  48. Stover PJ (2009) One-carbon metabolism–genome interactions in folate-associated pathologies. J Nutr 139(12):2402–2405CrossRefPubMedPubMedCentralGoogle Scholar
  49. U.S. Department of Agriculture, Agricultural Research Service (2017) National Nutrient Database for Standard Reference, release 28. Available via Nutrient Data Laboratory home page.
  50. US Department of Health and Human Services FaDA (1996) Food standards: amendment of the standards of identity for enriched grain product to require addition of folic acid. Fed Regist 16:8781Google Scholar
  51. van Engeland M, Weijenberg MP, Roemen GM, Brink M, de Bruine AP, Goldbohm RA et al (2003) Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: The Netherlands cohort study on diet and cancer. Cancer Res 63(12):3133–3137PubMedGoogle Scholar
  52. Voelter-Mahlknecht S (2016) Epigenetic associations in relation to cardiovascular prevention and therapeutics. Clin Epigenetics 8:4CrossRefPubMedPubMedCentralGoogle Scholar
  53. Wajed SA, Laird PW, DeMeester TR (2001) DNA methylation: an alternative pathway to cancer. Ann Surg 234(1):10–20CrossRefPubMedPubMedCentralGoogle Scholar
  54. Waki T, Tamura G, Sato M, Terashima M, Nishizuka S, Motoyama T (2003) Promoter methylation status of DAP-kinase and RUNX3 genes in neoplastic and non-neoplastic gastric epithelia. Cancer Sci 94(4):360–364CrossRefPubMedGoogle Scholar
  55. Wang YC, Yu ZH, Liu C, Xu LZ, Yu W, Lu J et al (2008) Detection of RASSF1A promoter hypermethylation in serum from gastric and colorectal adenocarcinoma patients. World J Gastroenterol 14(19):3074–3080CrossRefPubMedPubMedCentralGoogle Scholar
  56. Ward M (2001) Homocysteine, folate, and cardiovascular disease. Int J Vitam Nutr Res 71(3): 173–178CrossRefPubMedGoogle Scholar
  57. Winawer S, Fletcher R, Rex D, Bond J, Burt R, Ferrucci J et al (2003) Colorectal cancer screening and surveillance: clinical guidelines and rationale – update based on new evidence. Gastroenterology 124(2):544–560CrossRefPubMedGoogle Scholar
  58. Winder AF (1998) Homocysteine and cardiovascular disease. J Clin Pathol 51(10):713CrossRefPubMedPubMedCentralGoogle Scholar
  59. Wu H, Zhang Y (2014) Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 156(1–2):45–68CrossRefPubMedPubMedCentralGoogle Scholar
  60. Ye M, Xia B, Guo Q, Zhou F, Zhang X (2007) Association of diminished expression of RASSF1A with promoter methylation in primary gastric cancer from patients of central China. BMC Cancer 7:120CrossRefPubMedPubMedCentralGoogle Scholar
  61. Ye T, Chen Y, Fang J (2010) DNA methylation biomarkers in serum for gastric cancer screening. Mini-Rev Med Chem 10(11):1034–1038CrossRefPubMedGoogle Scholar
  62. Zhao H, Li Q, Wang J, Su X, Ng KM, Qiu T et al (2012) Frequent epigenetic silencing of the folate-metabolising gene cystathionine-beta-synthase in gastrointestinal cancer. PLoS One 7(11):e49683CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Catherine A. Powell
    • 1
  • Gabriella Villa
    • 2
  • Trevor Holmes
    • 2
  • Mahua Choudhury
    • 1
  1. 1.Department of Pharmaceutical SciencesTexas A&M Health Science Center, Irma Lerma Rangel College of PharmacyCollege StationUSA
  2. 2.Department of Pharmaceutical SciencesTexas A&M Health Science Center, Irma Lerma Rangel College of PharmacyKingsvilleUSA

Personalised recommendations