METHYLATION IMBALANCE - WHAT CAN GO WRONG?

Several studies in the 1980s revealed that DNA methylation played a major part in both gene regulation and cell differentiation. Since then, further research has confirmed the role of abnormal methylation in the development and progression of various diseases. According to Manel Esteller, director of the Josep Carreras Leukaemia Research Institute and professor of genetics at the University of Barcelona, “DNA methylation is one of the main controllers for specific-tissue expression allowing the correct expression of a gene in the right organ or cell type.” He further added, “DNA methylation acts as a buffer to stabilise our genome and silence repetitive chromosomic regions. Many diseases show an alteration of DNA methylation that disrupts cellular activity.” Esteller’s research mainly focuses on alterations in DNA methylation, histone modifications and chromatin in human cancer. At present, he is working on establishing epigenome and epitranscriptome maps for normal and transformed cells.

The folate and methionine cycles involved in methylation highly depend on an adequate supply of many key nutrients, which act as cofactors and substrates.

Without an adequate supply of these nutrients, which include folate, vitamin B2, vitamin B6, vitamin B12, serine and choline, methylation imbalances can occur. Inadequate dietary intake of these nutrients, nutrient malabsorption and medications that deplete nutrient levels can cause methylation imbalances. Single nucleotide polymorphisms (SNPs) including MTHFR polymorphisms are also a significant contributor to methylation imbalances (see breakout box). Lifestyle factors such as chronic alcohol intake, cigarette smoking, stress, and environmental toxicity and exposure can also result in methylation imbalances.

Methylation imbalances result in a build-up of homocysteine and inadequate production of methionine and S-adenosylmethionine (SAMe) which is the major methyl donor in the body.

The consequences of high homocysteine, inadequate SAMe and defective methylation include vascular damage, increased oxidative stress, inflammation, damage to DNA and dysregulation of DNA repair, neurotoxicity, altered neurotransmitter metabolism, reduced detoxification and reduced endogenous antioxidant production.

This may translate into ADD/ADHD, allergies, autism spectrum disorders, bone fractures, cardiovascular disease, cancer, chronic viral infections, cognitive decline, diabetes, immune dysfunction, fertility issues, macular degeneration, migraine, mood disorders (including anxiety and depression), multiple sclerosis, neural tube defects, neuropathy, pregnancy complications and thyroid dysfunction.

The key nutrient for supporting methylation, and the folate and methionine cycles, is folate, also known as vitamin B9. Before incorporation into the folate cycle, folic acid undergoes enzymatic modification at several key steps to be transformed into dihydrofolate (DHF), then tetrahydrofolate (THF), then 5,10-methylene-THF and ultimately 5-methyl-THF (5-MTHF), the active form of folate. 5-MTHF is then able to donate its methyl group to homocysteine transforming it into methionine 

The key nutrient for supporting methylation, and the folate and methionine cycles, is folate, also known as vitamin B9. Before incorporation into the folate cycle, folic acid undergoes enzymatic modification at many key steps to be transformed into dihydrofolate (DHF), then tetrahydrofolate (THF), then 5,10-methylene-THF and ultimately 5-methyl-THF (5-MTHF), the active form of folate. 5-MTHF is then able to donate its methyl group to homocysteine transforming it into methionine.

References:

MTHFR Support Australia. Frequently asked questions. [Link] 
 
Lynch B. Methylation and MTHFR defects, 2012. [Link]
 
Miller AL. The methionine-homocysteine cycle and its effects on cognitive diseases. Altern Med Rev 2003;8(1):7-19.