Skip to main content
SpringerLink
Log in

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

  • Living reference work entry
  • First Online:
Handbook of Famine, Starvation, and Nutrient Deprivation

  • 390 Accesses

Abstract

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.

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

Access this chapter

Log in via an institution

Institutional subscriptions

Abbreviations

CDC:

Centers for Disease Control

CIMP:

CpG island methylator phenotype

CpG Island:

Cytosine–phosphate–Guanine Island

CVD:

Cardiovascular disease

DHFR:

Dihydrofolate reductase

DNA:

Deoxyribonucleic acid

DNMT:

DNA methyltransferase

dTMP:

Deoxythymidine monophosphate

dTTP:

Deoxythymidine triphosphate

dUMP:

Deoxyuridine monophosphate

dUTP:

Deoxyuridine triphosphate

5-MTHF:

5-Methyltetrahydrofolate

MTHFR:

Methylenetetrahydrofolate reductase

PABA:

Para-aminobenzoic acid

SAM:

S-adenosylmethionine

TET:

Ten–eleven translocation proteins

THF:

Tetrahydrofolate

WHO:

World Health Organization

References

  • Bailey LB, Gregory JF III (1999) Folate metabolism and requirements. J Nutr 129(4):779–782

    CAS  PubMed  Google Scholar 

  • Bardhan K, Liu K (2013) Epigenetics and colorectal cancer pathogenesis. Cancer 5(2):676–713

    Article  CAS  Google Scholar 

  • 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):183–203

    Article  CAS  PubMed  Google Scholar 

  • 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):75–81

    Article  CAS  PubMed  Google Scholar 

  • 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):3290–3295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1292–1296

    Article  CAS  PubMed  Google Scholar 

  • CDC (2016) Folic acid (webpage, updated 28 Dec 2016). https://www.cdc.gov/ncbddd/folicacid/recommendations.html

  • 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):823–831

    Article  CAS  PubMed  Google Scholar 

  • Choi SW, Friso S (2010) Epigenetics: a new bridge between nutrition and health. Adv Nutr 1(1):8–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clark SJ, Melki J (2002) DNA methylation and gene silencing in cancer: which is the guilty party? Oncogene 21(35):5380–5387

    Article  CAS  PubMed  Google Scholar 

  • 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):421–423

    PubMed  Google Scholar 

  • Crider KS, Bailey LB, Berry RJ (2011) Folic acid food fortification – its history, effect, concerns, and future directions. Nutrients 3(3):370–384

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):21–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duthie SJ (1999) Folic acid deficiency and cancer: mechanisms of DNA instability. Br Med Bull 55(3):578–592

    Article  CAS  PubMed  Google Scholar 

  • Ehrlich M (2002) DNA methylation in cancer: too much, but also too little. Oncogene 21(35):5400–5413

    Article  CAS  PubMed  Google Scholar 

  • Esteller M (2002) CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 21(35):5427–5440

    Article  CAS  PubMed  Google Scholar 

  • 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):299–302

    Article  PubMed  Google Scholar 

  • 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):265–273

    Article  CAS  PubMed  Google Scholar 

  • 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):27–33

    Article  CAS  PubMed  Google Scholar 

  • 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):863–879

    Article  CAS  PubMed  Google Scholar 

  • 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):11636–11653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):e309

    PubMed  PubMed Central  Google Scholar 

  • 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):1917–1922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim YI (2004) Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer? Cancer Epidemiol Biomark Prev 13(4):511–519

    CAS  Google Scholar 

  • 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):479–484

    Article  CAS  PubMed  Google Scholar 

  • Kruman II, Fowler AK (2014) Impaired one carbon metabolism and DNA methylation in alcohol toxicity. J Neurochem 129(5):770–780

    Article  CAS  PubMed  Google Scholar 

  • 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):11313–11320

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):e003768

    Article  PubMed  PubMed Central  Google Scholar 

  • Liew SC (2016) Folic acid and diseases – supplement it or not? Rev Assoc Med Bras 62(1):90–100

    Article  PubMed  Google Scholar 

  • Lindzon G, O’Connor DL (2007) Folate during reproduction: the Canadian experience with folic acid fortification. Nutr Res Pract 1(3):163–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mattson MP, Kruman II, Duan W (2002) Folic acid and homocysteine in age-related disease. Ageing Res Rev 1(1):95–111

    Article  CAS  PubMed  Google Scholar 

  • Medici V, Halsted CH (2013) Folate, alcohol, and liver disease. Mol Nutr Food Res 57(4):596–606

    Article  CAS  PubMed  Google Scholar 

  • Messerschmidt DM, Knowles BB, Solter D (2014) DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos. Genes Dev 28(8):812–828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):11991–12006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niculescu MD, Zeisel SH (2002) Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr 132(Suppl 8):2333S–2335S

    CAS  PubMed  Google Scholar 

  • NIH (2016) Folate: dietary supplement fact sheet 2016. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/#en7

  • Pacchierotti F, Spano M (2015) Environmental impact on DNA methylation in the germline: state of the art and gaps of knowledge. Biomed Res Int 2015:123484

    Article  PubMed  PubMed Central  Google Scholar 

  • Pasechnikov V, Chukov S, Fedorov E, Kikuste I, Leja M (2014) Gastric cancer: prevention, screening and early diagnosis. World J Gastroenterol 20(38):13842–13862

    Article  PubMed  PubMed Central  Google Scholar 

  • Pitkin RM (2007) Folate and neural tube defects. Am J Clin Nutr 85(1):285S–288S

    CAS  PubMed  Google Scholar 

  • 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):1240–1248

    Article  CAS  PubMed  Google Scholar 

  • Qu Y, Dang S, Hou P (2013) Gene methylation in gastric cancer. Clin Chim Acta 424:53–65

    Article  CAS  PubMed  Google Scholar 

  • Quintero-Ronderos P, Montoya-Ortiz G (2012) Epigenetics and autoimmune diseases. Autoimmune Dis 2012:593720

    PubMed  PubMed Central  Google Scholar 

  • Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6(8):597–610

    Article  CAS  PubMed  Google Scholar 

  • Rosenquist TH (2013) Folate, homocysteine and the cardiac neural crest. Dev Dyn 242(3):201–218

    Article  CAS  PubMed  Google Scholar 

  • Scaglione F, Panzavolta G (2014) Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica 44(5):480–488

    Article  CAS  PubMed  Google Scholar 

  • Shorter KR, Felder MR, Vrana PB (2015) Consequences of dietary methyl donor supplements: is more always better? Prog Biophys Mol Biol 118(1–2):14–20

    Article  CAS  PubMed  Google Scholar 

  • Smith ZD, Meissner A (2013) DNA methylation: roles in mammalian development. Nat Rev Genet 14(3):204–220

    Article  CAS  PubMed  Google Scholar 

  • Stover PJ (2009) One-carbon metabolism–genome interactions in folate-associated pathologies. J Nutr 139(12):2402–2405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • U.S. Department of Agriculture, Agricultural Research Service (2017) National Nutrient Database for Standard Reference, release 28. Available via Nutrient Data Laboratory home page. http://www.ars.usda.gov/nutrientdata

  • 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 16:8781

    Google Scholar 

  • 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):3133–3137

    PubMed  Google Scholar 

  • Voelter-Mahlknecht S (2016) Epigenetic associations in relation to cardiovascular prevention and therapeutics. Clin Epigenetics 8:4

    Article  PubMed  PubMed Central  Google Scholar 

  • Wajed SA, Laird PW, DeMeester TR (2001) DNA methylation: an alternative pathway to cancer. Ann Surg 234(1):10–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):360–364

    Article  CAS  PubMed  Google Scholar 

  • 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):3074–3080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ward M (2001) Homocysteine, folate, and cardiovascular disease. Int J Vitam Nutr Res 71(3): 173–178

    Article  CAS  PubMed  Google Scholar 

  • 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):544–560

    Article  PubMed  Google Scholar 

  • Winder AF (1998) Homocysteine and cardiovascular disease. J Clin Pathol 51(10):713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu H, Zhang Y (2014) Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 156(1–2):45–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 7:120

    Article  PubMed  PubMed Central  Google Scholar 

  • Ye T, Chen Y, Fang J (2010) DNA methylation biomarkers in serum for gastric cancer screening. Mini-Rev Med Chem 10(11):1034–1038

    Article  CAS  PubMed  Google Scholar 

  • 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):e49683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

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

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Texas A&M Health Science Center, Irma Lerma Rangel College of Pharmacy, College Station, TX, USA

    Catherine A. Powell & Mahua Choudhury

  2. Department of Pharmaceutical Sciences, Texas A&M Health Science Center, Irma Lerma Rangel College of Pharmacy, Kingsville, TX, USA

    Gabriella Villa & Trevor Holmes

Authors
  1. Catherine A. Powell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabriella Villa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Trevor Holmes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mahua Choudhury
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mahua Choudhury .

Editor information

Editors and Affiliations

  1. Diabetes & Nutritional Sci Div Sch, King's College London, London, United Kingdom

    Victor Preedy

  2. Clinical Biochemistry, University of Westminster, Westminster, United Kingdom

    Vinood B. Patel

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this entry

Cite this entry

Powell, C.A., Villa, G., Holmes, T., Choudhury, M. (2018). Folate: Could We Live Without It? A Novel Epigenetic Connection. In: Preedy, V., Patel, V. (eds) Handbook of Famine, Starvation, and Nutrient Deprivation. Springer, Cham. https://doi.org/10.1007/978-3-319-40007-5_22-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-40007-5_22-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-40007-5

  • Online ISBN: 978-3-319-40007-5

  • eBook Packages: Springer Reference MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation