Epigenetic Shifts: How DNA Methylation Influences Gene Activity
Updated: 5 days ago
Written by Julia Haimovich, APD, CEDC - FerFit Dietetics & NutritionPublished: 14 September 2026 |Last reviewed: 14 September 2026
Your DNA provides the genetic instructions your cells use, but DNA sequence alone does not determine when and how every gene is used.
Epigenetics describes chemical and structural changes that influence gene activity without changing the underlying DNA sequence. These processes are important in normal development and cell function and can also be influenced by factors such as ageing, nutrition and environmental exposures.
One of the best-studied epigenetic mechanisms is DNA methylation. It involves the addition of small chemical groups called methyl groups to specific regions of DNA. Methylation forms part of a much larger network of reactions known as one-carbon metabolism, which relies on nutrients including folate, vitamin B12, vitamin B6 and choline.
Genes involved in this pathway, including MTHFR, can influence how some of these reactions occur. However, common MTHFR variants are only one part of a complex biological system and should not be interpreted as a diagnosis on their own.
Q1. What is Epigenetics and Why Does It Matter?
Epigenetics is the study of changes that affect how genes function without altering the DNA sequence itself.[1]
Epigenetic mechanisms include DNA methylation, modifications to proteins called histones and changes in how DNA is packaged inside cells.
These mechanisms help cells control which genes are more or less active. This is one reason cells containing essentially the same DNA can develop very different functions, such as muscle, nerve or liver cells.
Diet, ageing, smoking and other environmental exposures may influence parts of the epigenome, although the relationship between lifestyle and individual epigenetic changes is complex.[1,2]
Research has also identified altered DNA methylation patterns in conditions including cancer and some neurological and metabolic diseases. This does not mean that methylation changes are always the cause of disease; they may be a cause, consequence or marker of another biological process.
Q2. What is the MTHFR Gene?
MTHFR, or methylenetetrahydrofolate reductase, is a gene that provides instructions for making an enzyme involved in folate metabolism.[3]
This enzyme helps convert folate into a form used in the remethylation of homocysteine to methionine.
Methionine can then be used to produce S-adenosylmethionine (SAM), an important methyl donor used in many reactions throughout the body, including DNA and histone methylation.
Some people carry common variations in the MTHFR gene that can alter the activity of the enzyme.
Q3. How Common Are MTHFR Variants?
The two most commonly discussed MTHFR variants are C677T and A1298C.[3,4]
These variants are common in the population, although their frequency differs between ancestry and population groups.
A person may inherit no copies, one copy or two copies of a particular variant.
The C677T variant can reduce MTHFR enzyme activity, particularly when two copies are inherited. However, having a common MTHFR variant does not automatically mean that someone has a health problem or impaired methylation throughout their body.
Folate intake, vitamin B12 status, other genes, medications, health conditions and many other factors also influence one-carbon metabolism.
Q4. Can MTHFR Variants Cause Health Problems?
Research has investigated associations between MTHFR variants, homocysteine concentrations and a wide range of health conditions.
However, an association does not necessarily mean that an MTHFR variant directly causes a condition.
For example, some MTHFR variants may contribute to higher homocysteine concentrations, particularly when folate status is low. The clinical importance of this varies considerably between individuals.
Common MTHFR variants should therefore not be used on their own to explain symptoms such as fatigue, anxiety, depression, digestive problems or hormonal symptoms.
Major genetics organisations have also advised against routine MTHFR testing as part of thrombophilia investigations because common variants generally have limited clinical usefulness for predicting blood-clotting risk.[5]
Q5. What is Histamine and How Does It Relate to Methylation?
Histamine is a chemical messenger involved in immune responses, stomach acid secretion and signalling within the nervous system.
The body breaks histamine down through several pathways. One involves the enzyme histamine N-methyltransferase (HNMT), which uses a methyl group supplied by SAM. Another enzyme, diamine oxidase (DAO), helps break down histamine, particularly outside cells.
Because one histamine pathway uses methylation, there is a biochemical connection between histamine metabolism and one-carbon metabolism.
However, a blood histamine result cannot reliably tell you whether your whole body is “overmethylated” or “undermethylated.”
There is currently no universally accepted blood histamine range that diagnoses a person's overall methylation status.
Q6. What Does Methylation Do?
Methylation means transferring a methyl group one carbon atom attached to three hydrogen atoms onto another molecule.
Different methylation reactions perform different functions.
DNA methylation helps regulate gene activity, while methylation reactions elsewhere in the body are involved in the metabolism of neurotransmitters, hormones, proteins, lipids and other compounds.
One-carbon metabolism produces SAM, which acts as a major methyl donor for many of these reactions.[2,6]
Folate, vitamin B12, vitamin B6, choline, betaine and methionine all interact with parts of this metabolic network.
This is why adequate nutrition is important for normal one-carbon metabolism, but it does not mean that increasing methyl-donor supplements will necessarily improve health or increase beneficial DNA methylation.
Q7. What Do “Overmethylation” and “Undermethylation” Mean?
The terms overmethylation and undermethylation are sometimes used in complementary or functional-health discussions to categorise people according to symptoms or blood histamine concentrations.
These are not established medical diagnoses, and methylation throughout the human body cannot currently be reduced to a single high or low measurement.
DNA methylation also varies substantially between genes, tissues and cell types. Increased methylation in one region of DNA can have a very different biological effect from increased methylation somewhere else.
Symptoms such as anxiety, fatigue, poor concentration, insomnia, headaches or digestive problems have many possible causes and should not automatically be attributed to methylation.
For the same reason, supplements such as SAMe, methylfolate, methionine or betaine should not be started solely because someone believes they are an “under-” or “overmethylator.”
Q8. Why Is Homocysteine Important?
Homocysteine is an amino acid produced during methionine metabolism.
The body normally recycles or converts homocysteine using pathways that depend on nutrients including folate, vitamin B12 and vitamin B6.[7]
Higher homocysteine concentrations may occur with folate or vitamin B12 deficiency, but they can also be influenced by age, kidney function, thyroid function, medications, smoking and genetic factors.
MTHFR C677T can be one contributor, particularly in people with lower folate status.
A homocysteine result should therefore be interpreted together with a person's medical history and other relevant pathology rather than being treated as a direct measurement of methylation.
Laboratory reference intervals may also vary, so there is no single universal “optimal methylation” homocysteine number that applies to everyone.
Q9. What Is Trimethylglycine (TMG)?
Trimethylglycine, also called betaine, is a naturally occurring compound involved in one-carbon metabolism.
Betaine can donate a methyl group that helps convert homocysteine back into methionine through an alternative pathway.
Food sources include beetroot, spinach and some whole grains.
Betaine supplementation has been shown to lower homocysteine in some circumstances. However, this does not mean everyone with an MTHFR variant or elevated homocysteine needs a betaine supplement.
Supplementation should be considered in the context of a person's diet, pathology results, medical history and other supplements or medications.
Q10. Should You Test Your Methylation or MTHFR Status?
There is currently no single routine blood or urine test that measures a person's overall “methylation status.”
Useful investigations depend on the clinical question.
A healthcare professional may sometimes assess:
vitamin B12
folate
homocysteine
full blood count
iron studies or other relevant nutrient markers
kidney or thyroid function where clinically indicated.
MTHFR genetic testing is available, but finding C677T or A1298C does not by itself diagnose a methylation disorder or determine which supplements someone should take.
Organic acid tests and broad commercial genetic panels should also not be considered substitutes for appropriate medical assessment or standard pathology.
Diet and Lifestyle Tips to Support Normal One-Carbon Metabolism
A varied diet usually provides the nutrients required for normal methylation and one-carbon metabolism.
Important foods include green leafy vegetables and legumes for folate; eggs, fish, meat or suitable fortified foods for vitamin B12 and choline; and a range of vegetables, whole grains, nuts and seeds.
Regular physical activity, avoiding smoking, moderating alcohol intake and maintaining an overall balanced dietary pattern also support general metabolic and cardiovascular health.
There is no good evidence that everyone concerned about methylation needs to eliminate gluten, dairy, non-organic foods or foods containing folic acid.
Restrictions should instead have a clear nutritional or medical reason.
Do People With MTHFR Variants Need to Avoid Folic Acid?
No.
Common MTHFR variants are not a reason to automatically avoid folic acid.[4]
People with MTHFR variants can still process folic acid, although the C677T variant can influence folate metabolism.
Importantly, folic acid is the form of folate with established evidence for reducing the risk of neural tube defects.
In Australia, people planning pregnancy are generally advised to take 400 micrograms of folic acid daily before conception and during early pregnancy, unless a healthcare professional recommends a different dose.[8]
Do not stop a prenatal vitamin or folic acid supplement because of an MTHFR result without discussing it with an appropriately qualified healthcare professional.
Conclusion
Epigenetics helps explain how cells regulate gene activity without changing the underlying DNA sequence.
DNA methylation is one important epigenetic mechanism, while one-carbon metabolism provides methyl groups required for DNA methylation and many other biochemical reactions.
MTHFR is part of this system, but common MTHFR variants are only one small part of a much larger picture.
Rather than treating an MTHFR result as a diagnosis, it is more useful to consider diet, folate and vitamin B12 status, homocysteine where clinically relevant, medications, medical history and other health factors together.
If you are concerned about folate, vitamin B12, homocysteine or nutrition following genetic testing, an Accredited Practising Dietitian or appropriate medical professional can help interpret the results in context and develop an evidence-based nutrition plan.
References
National Human Genome Research Institute. Epigenomics Fact Sheet. National Institutes of Health.
Amenyah SD, Hughes CF, Ward M, et al. Influence of nutrients involved in one-carbon metabolism on DNA methylation in adults: a systematic review and meta-analysis. Nutrition Reviews. 2020;78(8):647–666. doi:10.1093/nutrit/nuz094.
Raghubeer S, Matsha TE. Methylenetetrahydrofolate (MTHFR), the one-carbon cycle, and cardiovascular risks. Nutrients. 2021;13(12):4562. doi:10.3390/nu13124562.
Centers for Disease Control and Prevention. MTHFR Gene Variant and Folic Acid Facts. Updated 2026.
Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genetics in Medicine. 2013;15:153–156. Addendum published 2020.
Mentch SJ, Locasale JW. One carbon metabolism and epigenetics: understanding the specificity. Annals of the New York Academy of Sciences. 2016;1363(1):91–98. doi:10.1111/nyas.12956.
U.S. National Library of Medicine. Homocysteine Test. MedlinePlus Medical Test.
Healthdirect Australia. Folate. Australian Government-supported health information service.
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