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The Key Nutrients Needed for DNA Methylation and Why It Matters

DNA Methylation and nutrients needed

In this article, we look at key nutrients for DNA methylation, including those we need for the synthesis of essential enzymes involved in the methylation process.

Let’s start with the nutrients required for the synthesis of S-adenosylmethionine (SAM), the key methyl donor for DNA methylation.

Alongside methionine itself, we also require folate, choline, betaine, and vitamins B2, B6, and B12 for proper methylation. These nutrients act as precursors and contribute to the production of SAM, meaning that deficiencies in these nutrients can affect SAM availability and normal DNA methylation.

Folate

Typically, diets deficient in methylfolate have been associated with reduced levels of SAM, increased levels of s-adenosylhomocysteine (SAH), and decreased SAM/SAH ratios. Conversely, high doses of folate supplementation appear to increase methylation at certain loci (places on specific chromosomes). This is a prime example of the need to balance methylation rather than either over supplementing or removing it from our diet entirely.

In the case of folate, things become more interesting due to its role in the one-carbon cycle. As we know, folate must be processed through several distinct steps in order to provide the substrate needed to create SAM for use in the body. 

Most supplemental folate comes in the form of folic acid, which is easier to store and incorporate into foods. However, supplementation with folic acid may not be beneficial if an individual has an issue with their one-carbon cycle, as may be the case if they carry the common risk T allele of the C677T polymorphism in MTHFR

If the one-carbon cycle is ‘jammed’, attempting to push more folic acid through the pathway won’t work and will instead lead to an accumulation of folic acid or folate, with the negative health effects described above. In such individuals, it may, therefore, be preferable to supplement with alternative forms such as L-methylfolate, or some of the other nutrients discussed below, which offer a more targeted approach to supporting methylation.

Before you choose to supplement with a methylfolate supplement, or any B vitamin for that matter, see our guide to B vitamin supplements and cancer risk.

Methionine

Just as with a high folate diet, a diet high in methionine is also thought to increase DNA methylation. This is because more methionine means a bigger pool of SAM available for use in methylation processes. 

Animal products such as meat and dairy are the greatest dietary sources of methionine. As such, diets especially rich in these foods can lead to hypermethioninemia (too much methionine), which is associated with the development of neurological issues and certain cancers.

Accordingly, diets with a lower, but still sufficient, methionine content have been linked to increased lifespan and improved health in certain animal models.1 2 However, individual genetic variation and environmental factors makes it difficult to define a one-size-fits-all dose for dietary methionine.

Betaine

Betaine, or trimethylglycine, is another important methyl donor and can be produced by choline or acquired through food. An amino acid derivative, betaine is typically sourced from plants. Sugar beets are an especially rich source of betaine, hence the name. 

As we know, remethylation of homocysteine is a major part of the methionine cycle. One process uses the enzyme methionine synthase (MS), which requires vitamin B12 as a co-factor and also depends indirectly on folate and other B vitamins. However, there is a second pathway that uses the enzyme betaine-homocysteine methyltransferase (BHMT) and requires betaine as a co-factor.

Betaine can then be further processed by the enzyme dimethylglycine dehydrogenase to produce folate, which can then be incorporated into the wider methylation cycle. As such, betaine is very important in cases where the traditional pathway for regenerating methionine has been compromised, as may occur in individuals with polymorphisms in the MS or MTHFR gene.

Choline

What about choline? While choline is a key nutrient in its own right, it also plays a major role in the methylation process in two distinct ways. First, choline is an important precursor molecule for betaine. Maintaining sufficient levels of choline is, therefore, essential for keeping this part of the pathway moving. Second, choline is typically converted to phosphatidylcholine, which is used by cells throughout the body to form their cell membranes and to synthesize neurotransmitters.

The enzyme Phosphatidylethanolamine N-Methyltransferase (PEMT) can also create phosphatidylcholine by converting phosphatidylethanolamine. This process is also involved in the formation of homocysteine from methionine. If PEMT cannot function because levels of phosphatidylcholine are too high, due to a very high dietary choline intake, then this pathway can stall, leading to difficulty generating new SAM molecules. However, choline methyl-deficient diets have also been linked to reductions in SAM and increased levels of SAH, suggesting alterations in DNA methylation pathways. 

Just to further show the complexity of methylation and nutrition, a dietary folate deficiency may lower choline and betaine levels in the liver, while choline deficiency may decrease liver folate stores, thereby affecting methyl transfer in the liver. Clear as mud, right?

Vitamin B2

Vitamin B2 (riboflavin) acts as a coenzyme and plays a major role in the production of the body’s main energy molecule adenosine triphosphate (ATP). Vitamin B2 is also the major co-factor for the MTHFR enzyme, which is key to regulating the one-carbon pathway and wider methylation cycle. 

Without adequate amounts of B2, MTHFR activity slows down, which can lead to a decrease in SAM and, therefore, reduced global methylation. Too little B2 can also lead to the accumulation of SAH, with its associated health impacts. 

Luckily, deficiencies in B2 are uncommon in the West as many processed foods are enriched with the vitamin. However, individuals who carry one of the risk alleles for the various polymorphisms in MTHFR may wish to consider supplementation to ensure the adequate function of this gene.

Vitamin B6

Let’s look now at vitamin B6 (pyridoxine) and a different part of the methylation cycle. Within the one-carbon pathway, vitamin B6 acts as a co-factor for SHMT, which sits before MTHFR in the cycle. As such, low levels of B6 may slow down the pathway as THF isn’t processed to 5,10-MTHF quickly enough for MTHFR’s requirements. 

Vitamin B6 also has other functions in the methylation cycle, this time involving homocysteine remethylation. As we’ve seen, methionine and homocysteine sit at opposite ends of the methionine cycle. While both methionine and homocysteine play an important role in DNA methylation, excessive levels of homocysteine are associated with several negative health effects.

Excess homocysteine can be cleared through the action of two enzymes known as cystathionine beta and gamma ligase. And this is where vitamin B6 comes in. Both enzymes use vitamin B6 as a co-factor. As such, a lack of B6 slows the activity of these enzymes, resulting in an accumulation of homocysteine.

Outside of methylation related co-factor effects, B6 is also vital in the synthesis of amino acids and important neurotransmitters such as serotonin, dopamine and GABA. Levels of these chemicals can be significantly affected by altered methylation pathways. This means that anyone carrying risk alleles for any of the polymorphisms in the wider methylation cycle may wish to consider supplementation of vitamin B6 to support the cycle as a whole, including supporting homocysteine regulation and neurotransmitter synthesis.

Vitamin B12

Last but not least in our round-up, vitamin B12 (cobalamin). This nutrient plays a key role in DNA synthesis, putting it right at the heart of epigenetics and methylation. B12 also sits at the heart of the methionine cycle, acting as the substrate for MS which is the main pathway for processing homocysteine to methionine. In the absence of vitamin B12, MS activity stalls, homocysteine accumulates, and SAM levels are reduced, leading to an overall reduction in methylation activity.

So, what’s the takeaway here?

Ultimately, most of the studies currently available have not shown how methyl donors lead to aberrant DNA methylation. Instead, these studies often rely heavily on assumptions about biological mechanisms. It seems, then, that there is no simple correlation between methyl donors and DNA methylation, with more research needed to figure out underlying mechanisms and to better understand patterns of DNA methylation in cells.

What we do know is that many of the enzymes that play a major role in the folate cycle (MTHFR, MTR, MS, SHMT, etc.) are regulated by micronutrients such as vitamins B2 (riboflavin), B6 (pyridoxine), and B12 (cobalamin). It is assumed that ensuring an optimal intake of these micronutrients may help to regulate DNA methylation. The bioavailability of these micronutrients may also affect DNA methylation, and DNA methylation may affect the bioavailability of these nutrients in some individuals.

Importantly, low intake of folate, methionine, B2, B6, B12 and niacin have been associated with increased risk of cancer, possibly by inducing abnormal DNA methylation and inhibition of DNA methyltransferases (DNMTs).

Dr. Aaron Gardner, BSc, MRes, PhD

Dr. Aaron Gardner, BSc, MRes, PhD is a life-scientist with a strong background in genetics and medical research, and the developing fields of personalized medicine and nutrition. Read his full bio here.

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