8.4) Methylation

Methylation is the process of introducing a methyl group to a molecule or compound. 

It is a mechanism that cells use to control gene expression by suppressing genes or turning them off.

DNA methylation is vital cellular process in our bodies intimately connected to our overall wellbeing. It is one of several mechanisms that cells use to control gene expression by suppressing genes or turning them off. When your methylation is working properly, you’re more likely to feel energetic and in a good mood. When it’s not working properly, you might feel tired, depressed, irritable or run-down.

Many health factors can affect your methylation process such as malabsorption of food (Celiac Disease, leaky gut), diseases of the bowel (Inflammatory Bowel Disease or Crohn’s Disease), kidney dialysis, liver disease, certain anemias, alcohol abuse, pregnancy and lactation (breastfeeding).

Methylation is essential for your normal development and is associated with key processes including genome stability, gene regulation, X-chromosome inactivation, aging and carcinogenesis. Methylation changes the activity of DNA. Research shows that variation in the function of enzymes involved in methylation can increase your risk of high homocysteine, chronic fatigue, mood disorders and neurodegeneration, diabetes, aging in general, heart disease and cancer. Individuals with multiple risk factors should take greater action to optimize health.

This section evaluates genetic variations that play a key role in methylation (see diagram below). The genetic variations tested are central to the formation of one of the body’s major methyl donors, s-adenosylmethionine (SAMe), as well as to the conversion of homocysteine into methionine – a reaction heavily dependent on folate (vitamin B9) and cobalamin (vitamin B12).

Nutrients from your food act as methylation co-factors. You can support methylation by eating a nutrient-rich diet and adding in supplementation where necessary. To support optimal methylation, provide your body with all of the methylation co-factors it requires including:

  • Folate found in vegetables (especially dark green leafy vegetables), fruits and fruit juices, nuts, beans, peas, seafood, eggs, dairy products, meat, poultry, and grains 
  • Other B vitamins, including vitamins found in salmon, trout, leafy greens, eggs, legumes, shellfish, meat, poultry, dairy, nutritional yeast, sunflower seeds
  • Dietary methionine, found in brazil nuts, large white beans, quinoa, turkey and grass-fed beef
  • Betaine, found in foods, including wheat, shellfish, spinach, and beets.

Figure 8-1 The folate and methionine cycles involve vitamins B2, B3, B6, B9 (folate), B12, betaine, and methionine. [Image source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471069/pdf/nutrients-11-00608.pdf]

8.4.1 Methylation - FUT2

How effectively you absorb cobalamin (vitamin B12) essential for methylation

Fucosyltransferase 2 (FUT2) encodes a precursor for the blood group ABO antigens found in the epithelial tissues, mucus membrane of the stomach and salivary glands. Your FUT2 secretor status has been shown to affect your ability to absorb vitamin B12.

Vitamin B12 is essential for methylation, it is required for the transfer of methyl groups. Specifically, vitamin B12 is a cofactor in the conversion of homocysteine and methylmalonyl-Co-A. Without adequate vitamin B12 the efficiency of these steps is reduced and results in measurably increased concentrations of homocysteine and methylmalonyl Co-A. Vitamin B12 deficiency is related to a number of various complex diseases including impaired immune defense, cardiovascular, gastrointestinal, and neurological disorders.

Variations in this panel affect how efficiently you absorb vitamin B12, an essential co-factor for methylation. Absorption of vitamin B12 from food requires a healthy digestive system. Individuals age 50 and above may have decreased intrinsic factor and therefore a reduction in the ability to absorb vitamin B12.

If you have risk for vitamin B12 deficiency, you may want to consider the following to improve your health:

  • Eat foods rich in vitamin B12 like eggs, sardines, clams, fortified nutritional yeast, grass-fed meat and dairy.
  • Consider supplementing with a B vitamin complex that includes methylcobalamin. This version of vitamin B12 is pre-methylated which can increase bioavailability.
  • Support digestion to improve vitamin B12 absorption.
  • Speak to your healthcare provider about improving your digestion in order to maximize absorption of the vitamin through food, especially if you have gastrointestinal conditions like atrophic gastritis, ulcerative colitis, or Crohn’s disease.
  • Have your vitamin B12 and homocysteine levels tested, especially if you exhibit symptoms of vitamin B12 deficiency, such as fatigue, and are over 50 years old.

An example of a gene that has been associated with cobalamin absorption is:

FUT2: Encodes a Golgi stack membrane protein that is involved in the creation of a precursor of the H antigen, which is required for the final step in the soluble A and B antigen synthesis pathway.

8.4.2 Methylation - TCN2

How effectively you transport cobalamin (vitamin B12) essential for methylation

Transcobalamin 2 (TCN2) is the primary transport protein for vitamin B12. Vitamin B12 is bound to the transcobalamin protein and transported from the blood stream to cells throughout your body. 

Individuals with variations in this gene have an impaired ability to transport vitamin B12 from the bloodstream to cells, resulting in a deficiency in cellular vitamin B12. This less efficient transport of vitamin B12 can lead to an age-related increase in homocysteine. Absorption of vitamin B12 from food requires a healthy digestive system. Individuals age 50 and above may have decreased intrinsic factor and therefore a reduction in the ability to absorb vitamin B12.

If you have variation in this panel, you may want to consider the following to improve your health:

  • Eat foods rich in vitamin B12 like eggs, sardines, clams, fortified nutritional yeast, grass-fed meat and dairy.
  • Consider supplementing with a B vitamin complex that includes methylcobalamin. This version of vitamin B12 is pre-methylated which can increase bioavailability.
  • Support digestion to improve vitamin B12 absorption. 
  • Speak to your healthcare provider about improving your digestion in order to maximize absorption of the vitamin through food, especially if you have gastrointestinal conditions like atrophic gastritis, ulcerative colitis, or Crohn’s disease.
  • Have your vitamin B12 and homocysteine levels tested, especially if you exhibit symptoms of vitamin B12 deficiency, such as fatigue, and are over 50 years old.

An example of a gene that has been associated with cobalamin transport is:

TCN2: Facilitates the absorption of cobalamin from the terminal ileum enterocytes into portal circulation and thereafter, supports proper cell delivery.

8.4.3 Methylation - SHMT1

How effectively you convert folate (vitamin B9) derivative THF into 5,10-MTHF

Serine hydroxymethyltransferase 1 (SHMT1) is a vitamin B6 containing enzyme. It catalyzes the co-conversion of L-serine and tetrahydrofolate (THF) to glycine and 5, 10-methyl THF. These steps are necessary to generate the active form of folate (5-MTHF). In addition to mediating the flow of folate to the methionine cycle, SHMT1 provides precursors for DNA production and neurotransmitter biosynthesis.

Individuals with variations in this gene may experience a build-up of cytosolic SHMT1, this affects the availability of active folate for the conversion of homocysteine into methionine. This variant can lead to reduced circulating folate levels and increased homocysteine. Especially when combined with variations in the MTHFR gene (see next page), individuals are at risk for folate cycle dysfunction which may be related to cardiovascular disease, and carcinogenesis through oncogene overexpression and tumor suppressor gene inactivation.

If you have variation in this panel, you may want to consider the following to improve your health:

  • Increase intake of co-factor vitamin B6 rich foods including turkey, grass fed beef, bananas, chickpeas, potatoes, and pistachios.
  • Take care when preparing vitamin B6 rich foods as this vitamin is subject to processing loss of more that 50% in some foods during cooking and storing. Plant sources tend to lose less during processing, as they contain a more stable source than that found in animal foods.
  • Increase your intake of folate-rich foods from dark leafy green vegetables such as swiss chard, kale, watercress, spinach, dandelion, collard greens and beet greens. 
  • Increase other sources of folate-rich foods such as beans, peas, lentils, lemons, bananas, and melons.
  • Consider supplementing with a B vitamin complex that includes a methylated folate (5-methyltetrahydrofolate/5-MTHF). This version of vitamin B9 is pre-methylated which can increase bioavailability and bypass a potentially weak SHMT1.

An example of a gene that has been associated with converting folate (vitamin B9) derivative THF into 5,10-MTHF is:

SHMT1: Encodes the cytosolic form of serine hydroxymethyltransferase, a pyridoxal phosphate-containing enzyme that catalyzes the reversible conversion of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate.

8.4.4 Methylation - MTHFR

How effectively you metabolize folate (vitamin B9) from food into its bioactive form

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate (5,10-MTHF) into 5- methyltetrahydrofolate (5-MTHF). This is an important step in the folate cycle and the methylation pathway because it determines the rate of the overall reaction.

Variations of the MTHFR gene inhibit the body’s ability to convert folate. Low folate intake affects individuals with variation in the MTHFR gene to a greater extent than those without. Individual with MTHFR variation have increased risk for elevated homocysteine levels, which can be mitigated with adequate folate intake. Folate deficiency and high homocysteine have been associated with a series of diseases and conditions, including cardiovascular disorders, psychiatric disorders, diabetes, neurological defects, some forms of cancer, male infertility, pregnancy complications, and birth defects including Down’s syndrome.

Individuals with MTHFR variation may benefit from supplementation with a form of folate that is pre-methylated (5-MTHF) – bypassing the MTHFR enzyme.

If you have a variation in this panel, you may want to consider the following to improve your health:

  • Increase your intake of folate-rich foods from dark leafy green vegetables such as swiss chard, kale, watercress, spinach, dandelion, collard greens and beet greens. 
  • Increase other sources of folate-rich foods such as beans, peas, lentils, lemons, bananas, and melons.
  • Improve folate absorption with vitamin C from fruit and vegetable sources including plum, rose hip, blackcurrant, bell pepper, kale and broccoli.
  • Include dietary sources of methylation cofactors including vitamins B2, B3, B6 and B12. Sources include salmon, leafy greens, eggs, grass-fed beef, shell fish and legumes.
  • Consider supplementing with a B vitamin complex that includes a methylated folate. Look for labels which read 5-methyltetrahydrofolate or 5-MTHF (which are pre-methylated and more bioavailable).

An example of a gene that has been associated with metabolizing folate (vitamin B9) into its bioactive form is:

MTHFR: Encodes the MTHFR enzyme, catalyzing the conversion of 5,10-methylenetetrahydrofolate to active folate, 5-methylenetetrahydrofolate (5-MTHF or L-MTHF). 5-MTHF is then utilized as a co-substrate for the conversion of homocysteine to methionine and in the production of the methyl donor S-adenosylmethionine (SAMe). In simpler terms, this gene produces an enzyme that adds a methyl group to folate to make it usable by the body. It is a key player in folate metabolism. Methyl donors are vital for detoxification, DNA repair and synthesis, neurotransmitter and hormone metabolism. Variations in MTHFR is associated with decreased enzyme activity and require more dietary folate. Sufficient vitamin C has been shown to improve folate absorption.

8.4.5 Methylation - MTR

How efficiently you transform homocysteine into methionine

Methionine Synthase (MTR) converts homocysteine back into methionine, preventing the negative build-up of homocysteine in the blood and supplying the methionine integral for DNA methylation to occur. Methionine in turn drives the production of S-adenosylmethionine (SAMe) – one of the primary methyl donors for a host of enzymatic reactions.

MTR requires a methylated form of vitamin B12 (methylcobalamin) and another enzyme called methionine synthase reductase, which is produced from the MTRR gene (more details on the next page). Without these cofactors MTR cannot convert homocysteine to methionine. This pathway is important because it is the main pathway responsible for homocysteine recycling.

The impact of this variant on DNA methylation is debated in literature. This variant has been associated with congenital birth defects including spina bifida, cleft palate and cardiac defects. To reduce risk, ensure adequate intake of folate cycle and methylation co-factors.

If you have a variation in this panel, you may want to consider the following to improve your health:

  • Eat foods rich in vitamin B12 like eggs, sardines, clams, fortified nutritional yeast, grass-fed meat and dairy.
  • Ensure adequate intake of trace mineral zinc found in shellfish, seeds and legumes such as lentils, chickpeas and beans.
  • Consider supplementing with a B vitamin complex that includes methylcobalamin. This version of vitamin B12 is pre-methylated which can increase bioavailability.
  • Support digestion to improve vitamin B12 absorption. 
  • Speak to your healthcare provider about improving your digestion in order to maximize absorption of vitamin B12 through food, especially if you have gastrointestinal conditions like atrophic gastritis, ulcerative colitis, or Crohn’s disease.
  • Have your vitamin B12 and homocysteine levels tested, especially if you exhibit symptoms of vitamin B12 deficiency, such as fatigue, and are over 50 years old.

An example of a gene that has been associated with transforming homocysteine into methionine is:

MTR: Catalyzes the conversion of homocysteine to methionine. MTR uses methylcobalamin (methyl B12) as the methyl donor in this reaction. Methionine in turn drives the production of S-adenosylmethionine (SAMe) – one of the primary methyl donors for a host of enzymatic reactions.

8.4.6 Methylation – MTRR

How efficiently you methylate cobalamin (vitamin B12) to methylcobalamin

The collaboration of Methionine Synthase Reductase (MTRR) and the MTR (from the previous page) play an essential role in the conversion of homocysteine to methionine. After a period of being active, MTR becomes inactive. MTRR reactivates MTR.

Individuals with variation in this panel have a reduced enzymatic efficiency and in turn the effectiveness with which vitamin B12 is re-methylated is diminished. These individuals have an increased risk for diseases related to vitamin B12 deficiency and homocysteine accumulation.

If you have a variation in this panel, you may want to consider the following to improve your health:

  • Eat foods rich in vitamin B12 like eggs, sardines, clams, fortified nutritional yeast, grass-fed meat and dairy.
  • Ensure adequate intake of trace mineral zinc found in shellfish, seeds and legumes such as lentils, chickpeas and beans.
  • Consider supplementing with a B vitamin complex that includes methylcobalamin. This version of vitamin B12 is pre-methylated which can increase bioavailability.
  • Support digestion to improve vitamin B12 absorption. 
  • Speak to your healthcare provider about improving your digestion in order to maximize absorption of the vitamin through food, especially if you have gastrointestinal conditions like atrophic gastritis, ulcerative colitis, or Crohn’s disease.
  • Have your vitamin B12 and homocysteine levels tested, especially if you exhibit symptoms of vitamin B12 deficiency, such as fatigue, and are over 50 years old.

An example of a gene that has been associated with methylate cobalamin (vitamin B12) to methylcobalamin is:

MTRR: Encodes the MTRR enzyme. Variation within this gene affects its enzymatic efficiency and in turn the efficacy with which vitamin B12 is re-methylated (to act as the methyl donor for homocysteine to methionine conversion catalyzed by methionine synthase).

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