Chapter 5. The Importance of DNA Methylation in the Body


Deniz Karakçı
Department of Biochemistry, University of Tekirdag Namik Kemal, Faculty of Veterinary Medicine, Tekirdag, Turkey

Part of the book: Advances in Health and Disease. Volume 63


Methylation is the addition of a methyl group (CH3) to a chemical compound. This process, which is a chemical reaction, takes place in the systems that occur in the body. When a molecule goes through the process of methylation, then the molecule is ‘methylated.’ Biochemical molecules such as genes, enzymes, hormones, neurotransmitters, and vitamins are suitable for methylation. DNA and RNA synthesis and repairing, metabolism of neurotransmitters, proper functioning of the immune system, gene regulation, epigenetic mechanisms are some of the duties of methylation. Methylation, which regulates epigenetic events such as gene activation, repression and chromatin remodeling, and gene expression, occurs in two ways that are protein (histone) methylation and DNA methylation. Protein methylation occurs by adding a methyl group to the arginine and lysine amino acids. On the other hand, DNA methylation materializes when a methyl group is attached to the CpG sites in vertebrates with the DNA methyltransferase enzyme. Methylation reactions in the body may be impaired due to some reasons. To understand this degradation, it is necessary to give information about the MTHFR (Methylenetetrahydrofolate Reductase) enzyme, which is an important part of the methylation process. The MTHFR is an enzyme that adds a methyl group to folate to constitute the methyl folate form, also known as 5-MTHF, that the body can use. If there is a small mutation called single nucleotide polymorphism (SNP) in the gene with the same name as MTHFR enzyme, the function of this enzyme may slowdown. The MTHFR gene mutation is among the important factors that will negatively affect the methylation cycle. High homocysteine levels and low concentrations of folate and some other vitamins in the blood can lead to this genetic mutation. This gene mutation can be detected with tests. Gene mutations can pose a health risk in individuals who have bad living habits, such as stress, malnutrition, alcohol and drugs. This can cause inflammation, cardiovascular diseases, cancer, insulin resistance, paralysis, anxiety, depression, and digestive disorders. Those with MTHFR mutations need to change certain lifestyle choices that can increase homocysteine levels as a preventative measure. People with MTHFR mutations may avoid foods that contain folate, the synthetic form of folic acid, although the evidence is not clear what is necessary or helpful. Quality nutrition, exercise, and other healthy lifestyle habits will improve the general condition.

Keywords: methylation, MTHFR, epigenetic, gene


Bagley P J and Jacob S A. Common mutation in the methylenetetrahydrofolate reductase
geneis associated with an accumulation of formylated tetrahydrofolates in red blood
cells. Medical Sciences (1998) 95:13217-13220.
Baylin S B, Herman J G, Graff J R, Vertino P M, Issa J P. Alterations in DNA methylation:
a fundamental aspect of neoplasia. Advance Cancer Research. (1998) 72:141-96.
Bird A. DNA methylation patterns and epigenetic memory. Genes Development (2002)16:
Bird A. Il2 transcription unleashed by active DNA demethylation. Nature Immunology
(2003) 4:208- 9.
Bishop K S and Ferguson L R. The Interaction between Epigenetics. Nutrition and the
Development of Cancer Nutrients (2015) 7: 922-947 DOI:10.3390/nu7020922.
Bottiglieri T. Homocysteine and folate metabolism in depression. Progress
Neuropsychopharmacoogy Biological Psychiatry (2005) 29:1103-1.
Chang, H., Zhang, T., Zhang, Z., Bao, R., Fu, C., Wang, Z., Bao, Y., Li, Y., Wu, L., Zheng,
X., & Wu, J. (2011). Tissue-specific distribution of aberrant DNA methylation
associated with maternal low-folate status in human neural tube defects. The Journal
of Nutritional Biochemistry (2011) 22: 1172-1177.
Jia Chen, Marilie D Gammon, Wendy Chan, Caroline Palomeque, James G Wetmur,
Geoffrey C Kabat, Susan L Teitelbaum, Julie A Britton, Mary Beth Terry, Alfred I
Neugut, Regina M Santella. One-carbon metabolism, MTHFR polymorphisms, and
risk of breast cancer. Cancer Research (2005) 65:1606-1614.
Coppen A and Bolander-Gouaille C. Treatment of depression: time to consider folic acid
and vitamin B12. Journal of Psychopharmacology (2005) 19:59-65.
Costello J F, Plass C J. Methylation matters. Journal of Medical Genetics (2001) 38:285-303.
Cui H, Horon I L, Ohlsson R, Hamilton S R, Feinberg A P. Loss of imprinting in normal
tissue of colorectal cancer patients with microsatellite instability. Nature Medicine
(1998) 4:1276-1280.
Deng G, Kakar S, Okudiara K, Choi E, Sleisenger M H, Kim Y S. Unique Methylation
Pattern of Oncostatin M Receptor Gene in Cancers of Colorectum and Other Digestive
Organs. Cancer Research (2009) 15:1519-1526.
Dick, K. J., Nelson, C. P., Tsaprouni, L., Sandling, J. K., Aïssi, D., Wahl, S., Meduri, E.,
Morange, P.-E., Gagnon, F., Grallert, H., Waldenberger, M., Peters, A., Erdmann, J.,
Hengstenberg, C., Cambien, F., Goodall, A. H., Ouwehand, W. H., Schunkert, H.,
Thompson, J. R., Samani, N. J. (2014). DNA methylation and body-mass index: a
genome-wide analysis. Lancet (2014) 383:1990 -1998.
Duymich C E, Charlet J, Yang X, Jones P A and Liang G. DNMT3B isoforms without
catalytic activity stimulate gene body methylation as accessory proteins in somatic
cells. Nature Communications (2016) 7:1-9.
Dikmen M. Molecular biology of Methylenetetrahydrofolate Reductase (MTHFR) enzyme
and its association with diseases. The Medical Journal of Kocatepe (2004) 5:9-16.
Ellingrod, V. L., Taylor, S. F., Dalack, G., Grove, T. B., Bly, M. J., Brook, R. D., Zöllner,
S. K., & Pop-Busui, R. (2012). Risk factors associated with metabolic syndrome in
bipolar and schizophrenia subjects treated with antipsychotics: the role of folate
pharmacogenetics. Journal of Clinical Psychopharmacology (2012) 32:261-265.
Esteller M. Impact of DNA Methylation on Health and Disease. DNA Methylation:
Approaches, Methods, and Applications CRC Press LLC (2005) 1-11.
Simonetta Friso 1, Sang-Woon Choi, Domenico Girelli, Joel B Mason, Gregory G
Dolnikowski, Pamela J Bagley, Oliviero Olivieri, Paul F Jacques, Irwin H Rosenberg,
Roberto Corrocher, Jacob Selhub. common mutation in the 5,10-
methylenetetrahydrofolate reductase gene affects genomic DNA methylation through
an interaction with folate status. Proceedings of the National Academy of Sciences of
the USA (2002) 99: 5606-5611.
Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate Reductase (MTHFR) Genetic
Polymorphisms and Psychiatric Disorders: A Huge Review. Am. J. Epidemiol. (2007)
Grewal S I and Rice J C. Regulation of heterochromatin by histone methylation and small
RNAs. Current Opinion Cell Biology (2004) 16:230-238.
Gurdol F. Medicine Biochemistry. Nobel Medicine (2017) Press 3th Edition, Turkey.
Hesdorffer C S and Longo D L. Drug induced megaloblastic anemia The New England
Journal of Medicine (2015) 373(17):1649 1658. doi:10.1056/NEJMra1508861.
Hickey S E, Curry, C J and Toriello H V. American College of Medical Genetics Practice
guideline: Lack of evidence for MTHFR polymorphism testing. Genetics in Medicine
(2013) 15(2):153–156.
Homberger A, Linnebank M, Winter C, Willenbring H, Marquardt T, Harms E, Koch H G.
Genomic structure and transcript variants of the human methylenetetrahydrofolate
reductase gene. (2000) European Journal Human Genetic 8:725-729.
Jiménez-Chillarón J C, Díaz R, Martínez D, Pentinat T, Ramón-Krauel M, Ribó, S, Plösch
T. The role of nutrition on epigenetic modifications and their implications on health.
Biochimie (2012): 94: 2242-2263.
Jurkowska RZ and Jurkowski TP. Establishment, Erasure and Synthetic Reprogramming
of DNA Methylation in Mammalian Cells. The DNA, RNA, and Histone Methylomes
(2020) Springer, USA.
Kim Y I. Folate and colorectal cancer: An evidence-based critical review. Molecular
Nutrition Food Research (2007) 51: 267292.
Myoung Sook Kim 1, Joost Louwagie, Beatriz Carvalho, Jochim S Terhaar Sive Droste,
Hannah Lui Park, Young Kwang Chae, Keishi Yamashita, Junwei Liu, Kimberly
Laskie Ostrow, Shizhang Ling, Rafael Guerrero-Preston, Semra Demokan, Zubeyde
Yalniz, Nejat Dalay, Gerrit A Meijer, Wim Van Criekinge, David Sidransky. Promoter
DNA methylation of oncostatin m receptor-beta as a novel diagnostic and therapeutic
marker in colon cancer. PLoS One (2009) 4: e6555.
Kulis M and Esteller M. DNA Methylation and Cancer.
Advances in Genetics (2010) 70: 27-56.
Levin B L and Varga. E. MTHFR: Addressing Genetic Counseling Dilemmas Using
Evidence-Based Literature. Journal of Genetic Counseling (2016) 25 (5) :901-911.
Mann M R W, Bartolomei M S. Epigenetic reprogramming by maternal behaviour and
pharmalogical intervention nature versus nurture; let’s the whole thing off.
Epigenetics (2007) 2:22-28.
Nasim Mansoori, Manjari Tripathi, Kalpana Luthra, Rizwan Alam, Ramakrishnan
Lakshmy, Subhadra Sharma, Subramanyam Arulselvi, Shama Parveen, Asok K
Mukhopadhyay. MTHFR (677 and 1298) and IL-6-174 G/C genes in pathogenesis of
Alzheimer’s and vascular dementia and their epistatic interaction. Neurobiology Aging
(2012) 33:845-1020.
Moll S and Varga E A. Homocysteine and MTHFR Mutations. Circulation (2015) 132(1):
e 6-9 DOI: 10.1161/cırculatıonaha.114.013311.
Moore L D, Le T and Fan G. DNA Methylation and its basic function,
neuropsychopharmacology. Reviews (2013) 38: 23-38.
Kentaro Murakami 1, Tetsuya Mizoue, Satoshi Sasaki, Masanori Ohta, Masao Sato, Yumi
Matsushita, Norio Mishima. Dietary intake of folate, other B vitamins, and omega-3
polyunsaturated fatty acids in relation to depressive symptoms in Japanese adults.
Nutrition (2008) 24:140-147.
Nakayama J, Rice J C, Strahl B D, Allis C D, Grewal S I. Role of histone H3 lysine 9
methylation in epigenetic control of heterochromatin assembly. Science (2001)
Nelson D L. Lehninger principles of biochemistry: Fourth edition. New York: W. H.
Freeman, 2005.
Oner, C. Concepts Genetics, Palme Press (2011) 8th Edition, Turkey.
George I Papakostas 1, Timothy Petersen, Barry D Lebowitz, David Mischoulon, Julie L
Ryan, Andrew A Nierenberg, Teodoro Bottiglieri, Jonathan E Alpert, Jerrold F
Rosenbaum, Maurizio Fava. The relationship between serum folate, vitamin B12, and
homocysteine levels in major depressive disorder and the timing of improvement with
fluoxetine. International Journal Neuropsychopharmacology (2005) 8:523- 528.
F Peng 1, L A Labelle, B J Rainey, G J Tsongalis. Single nucleotide polymorpisms in the
methylenetetrahydrofolate reductase gene are common in US Caucasian and Hispanic
American populations. Intertainal Journal of Molecular Medicine (2001) 8:509-511.
Rai V. Evaluation of methylenetetrahydrofolate reductase gene variant (C677T) as risk
factor for bipolar disorder. Cell Molecular Biology (2011) (27) 57:558-1566.
Rountree M R, Bachman K E, Herman J G, Baylin S B. DNA methylation, chromatin
inheritance, and cancer Oncogene (2001) 20:3156-3165.
Rozen R. Molecular genetics of methylenetetrahydrofolate reductase deficiency. Journal
of Inherited Metabolic Disease (1996) 19(5): 589-594.
Song J, Medline A, Mason J B, Gallinger S, Kim Y I. Effects of dietary folate on intestinal
tumorigenesis in the apc Min mouse. Cancer Research (2000) 60: 5434-5440.
Teegarden D, Romieu I, Lelièvre S A. Redefining the impact of nutrition on breast cancer
incidence: Is epigenetics involved? Nutrition Research Reviews (2012) 25: 68-95.
Zeisel SH. Epigenetic mechanisms for nutrition determinants of later health outcomes. The
American Journal of Clinical Nutrition (2009) 89: 1488S-1493S.
Zhang M Y, Miao L, Li Y S, Hu G Y. Meta-analysis of the methylenetetrahydrofolate
reductase C677T polymorphism and susceptibility to Alzheimer’s disease. Neurosci.
Res. (2010) 68:142-150.
Zhao H Y, Kong Y, Ye M. Association between the MTHFR gene and Alzheimer’s disease:
a meta-analysis. Int. J. Neurosci. (2011) 121:462-741.
Zhao R, Diop-Bove N, Visentin M and Goldman ID. Mechanisms of membrane transport
of folates into cells and across epithelia. Annual Review of Nutrition (2011) 31: 177-
201. DOI: 10.1146/ annurev-nutr-072610-145133.


Publish with Nova Science Publishers

We publish over 800 titles annually by leading researchers from around the world. Submit a Book Proposal Now!

See some of our Authors and Editors