DNA Methylation
It is a process by which methyl groups are added to a DNA molecule.
This can change the activity of DNA without changing the sequence of the molecule.
In mammals, DNA methylation is an essential process required for normal development and is also associated with key processes like genomic imprinting, aging carcinogenesis, etc.
Methylation can occur only with 2 of DNA’s 4 bases i.e cytosine and adenosine.
Cytosine methylation is seen in both eukaryotes and prokaryotes, but its rate can vary widely.
Adenosine methylation, on the other hand, occurs in bacteria, plants and recently discovered in mammals as well.
DNA methylation occurs in three different sequences: CG, CHG or CHH, where H corresponds to Adenosine(A), Thymine(T) or Uracil/Guanine(U/G).
In mammals, DNA methylation occurs in the CG sequence with the cytosine of both strands being methylated.
The most common form of DNA methylation occurs at the 5-carbon position of cytosine –5 methylcytosine.
In mammals, 60-80% of the CG are methylated in the somatic cells and this high frequency of methylation is responsible for a large number of mutations, which cause genetic, metabolic and chronic diseases like cancer.
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Why is DNA methylation important?
DNA methylation is the primary basis of the chromatin structure and is usually found in the CpG dinucleotide region.
Methylation is proven to play a crucial role in regulating gene expression and these modifications occur at very specific locations within the genome of each species.
While DNA methylation is a regular thing and is essential for various cell processes, aberrant methylation can lead to the development of diseases.
Hand-picked content for you: Know Your Genes: MTHFR “Folic Acid Gene”
What does MTHFR deficiency mean?
MTHFR or Methylenetetrahydrofolate reductase is the rate-limiting enzyme in the methyl cycle and is responsible for the conversion of homocysteine into methionine.
A deficiency in this enzyme is said to be one of the most common causes of elevated levels of homocysteine.
It occurs due to genetic defects in the MTHFR, which is an important enzyme in the methyl cycle.
There are two common variants of MTHFR deficiency.
The more common one of the two is homologous for the 677T polymorphism.
The homologous 677T variant can increase the risk of some diseases.
Individuals who are homozygous in this variant tend to have an elevated risk of thromboembolism and stroke.
Children of such individuals stand to have an increased risk of neural tube defects.
The second variant of the MTHFR deficiency is a milder 1298C polymorphism which leads to 68% of the control values of enzyme activity and normally does not lead to low serum folate.
What is the effect of methylation?
DNA methylation is the transfer of methyl (-CH3)group to the DNA strand, often to the 5th carbon of the cytosine ring.
This conversion of cytosine to 5-methylcytosine is brought about by a special set of enzymes known as DNA methyltransferases.
Methylation is seen in all mammals and is essential for the normal growth and development of individuals.
It also enables the suppression of retroviral gene expressions and other potentially dangerous sequences of DNA that have entered and may have damaged the host. DNA methylation is responsible for the formation of chromatin structure.
Any aberration in the methylation process can lead to the development of various diseases.
What does methylation do to the body?
Methylation of proteins can change the way a protein reacts with other substances in the body.
It can affect enzymes, hormones, and genes.
In some instances, methylation of proteins helps to detoxify the body as seen in the case when homocysteine is methylated to methionine, which is a beneficial amino acid.
Methylation affects the efficiency of enzymes and also can turn genes on and off, which can impact our health positively and negatively.
What effect does methylation have on gene expression?
Studies show that methylation affects gene expression.
There is believed to be a correlation between gene transcription and undermethylation.
The presence of methyl moieties is also believed to inhibit gene expression.
Methylation influences gene expression by affecting the DNA of both chromatin proteins and specific transcription factors.
The methylation patterns are stable in somatic cells but in early embryonic stages, they are characterized by alteration in the DNA modification.
How can changes in gene expression lead to cancer?
Mutations are basically abnormal changes that occur in the DNA of a gene.
Mutations affect the DNA bases that form the genetic code.
Even a single base change can bring out a disastrous effect.
Different mutations bring about different types of effects– some prevent the formation of proteins, some affect the proteins' functions, some lead to diseases and others might not have any effects.
DNA methylation, modification of the histones, and RNA interference are few ways that affect gene expression and bring about mutations.
Some of these mutations can lead to the development of cancer in an individual.
What causes poor methylation?
There are multiple factors stated for poor methylation. These include:
- Nutritional deficiencies
- Changes in the gut microflora
- Reduction in competition for methyl donors due to environmental toxins, medications, stress, high level of estrogens, high intake of histamine, and chronic infections.
What causes undermethylation?
Every cell in our body needs methylation to grow and repair.
But, what happens when there is a shortage of methyl molecules?
This situation is called as undermethylation.
This causes a lot of different effects on the body.
Undermethylation reduces the production of two common neurotransmitters –serotonin and dopamine.
Undermethylation can occur to many factors like nutrient deficiency, change in the bacteria in the gut, medications, high stress, high intake of histamines, allergies and infections.
MTHFR mutations
MTHFR gene is one of the 20,000 genes a human being carries.
But, about 30-50% of the people also carry the MTHFR gene mutation.
Having this mutation puts these individuals at a high risk of cardiac disease, Alzheimer’s, colon cancer, etc.
When an individual has an MTHFR mutation, it changes the way one metabolizes and converts nutrients in the diet into minerals, and proteins one can use.
This mutation can also affect hormone and neurotransmitter levels, brain functioning, cholesterol levels, digestion and similar effects on other body systems and processes.
Few symptoms of MTHFR gene mutations include:
- Attention Deficit Hyperactivity Disorder
- Autism
- Cardiovascular conditions
- Fatigue
- Irritable Bowel Syndrome
- Hormonal imbalance and related conditions
- Schizophrenia
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How do you test for methylation?
With a lot of individuals at a high risk of sub-optimal methylation, it is important to know how one can test for it.
Complete blood count (CBC)
Large RBCs, anemia or RBCs with a Mean Corpuscular Volume(MCV) greater than 95% are signs of faulty methylation.
Homocysteine test
This is one of the important tests you will be advised if faulty methylation is suspected.
Homocysteine levels over 13 indicate a problem with methylation. The ideal value is between 6 and 8.
Urinary Amino Acid Test
This test is used to look for unusual metabolic disorders involving vitamins B6, folate and B12 that do not show up in a Homocysteine or methylmalonic acid test.
Urinary or Serum methylmalonic acid test
This test is a specific test to detect B12 insufficiency. The levels of the acid may get elevated even with a normal level of vitamin B12 or homocysteine levels.
What is the methylation test?
DNA methylation test enables the doctor to screen patients for a variety of genetic changes like SNPs, which affect the function of important biochemical processes.
The presence and absence of these SNPs are said to modify disease risk, which can be reduced or eliminated by making some lifestyle changes.
The SNPs in the methylation test profile include VDR, BHMT, COMT, MAO-A, AHCY, CBS, MTR, MTHFR, MTRR, SHMT, and SUOX.
How do you increase methylation naturally?
For individuals who have suboptimal or reduced methylation, there are some lifestyle changes they can make to naturally increase methylation.
This primarily includes dietary changes to include foods that promote and support methylation.
Some methylation promoting food items include:
- Dark green vegetables
- Beetroots
- Legumes
- Beans
- Mushrooms
- Okra or Lady’s finger
- Seeds like sesame seeds
- Cruciferous vegetables like cabbage
- Rosemary
- Berries
- Turmeric
How does methylation cause cancer?
DNA methylation is currently being widely studied.
It is known to be a normal part of genome functioning and any alteration in this process is said to affect the key functioning of the cells in an organism including development, differentiation, and gene expression.
However, alterations in the DNA methylation cycle is said to also be the underlying cause of many diseases, including cancer.
The methylation process in cancer cells is said to be different from that seen in normal cells, and this difference is responsible for the diagnosis of cancer.
It is believed that factors causing hypo or hypermethylation lead to changes in the process of DNA methylation.
These changes affect gene expression, cause gene mutations and thereby increase the risk of cancer development.
Does methylation tighten DNA?
Our body has more than 6 feet of DNA that are packed into each cell.
So, for the genes to get turned on or off, the DNA needs to be loosened up so that the cell can read the DNA sequences.
When methylation of DNA occurs, the cell can loosen or tighten the DNA in order to turn the genes 'on' or 'off'.
This is known as epigenetics.
What does methylation do to histones?
Histone methylation involves the modification of some amino acids like lysine and arginine in a histone protein by the addition of one, two or three methyl groups.
The methylation or demethylation of histones turns the genes in DNA ‘off’ and ‘on’ respectively.
Histone methylation is associated with transcriptional repression.
However, methylation of some lysine and arginine residues leads to transcription activation.
Does DNA methylation cause any damage to the body?
Methylation is brought about by methylating agents.
These agents modify DNA at different sites, thereby producing lethal lesions and disease conditions.
What supplements should I take for MTHFR deficiency?
To deal with MTHFR deficiency, you must include the following supplements in your diet:
- Eat foods that are rich in the vitamin and avoid synthetic supplements that contain folic acid. These include dark leafy greens like spinach, kale, etc.
- If your homocysteine levels are high, take vitamin B6, B12, and 5MTHF supplements.
- Try and stick to a hormone-free range of dairy and poultry products.
- If you have any amalgam dental fillings, get them removed and replaced with mercury-free fillings.
- Avoid high doses of vitamin B3 as it can be harmful to methylation.
Ensure you get a gentle detox regime throughout the week that includes regular exercises, Epsom salt baths, and infrared sauna.
What are methylated vitamins?
About 30% of the population is unable to metabolize the unmethylated forms of certain vitamin B, especially folate and vitamin B12.
So, active forms of vitamin B, known as the methylated form are given to these people as they can easily utilize this form of the vitamins.
Is choline a methyl donor?
Choline is an essential nutrient and a methyl donor involved in many physiological processes like metabolism, transport of lipids, methylation reactions, and neurotransmitter synthesis, etc.
Is methyl B12 healthy?
The active form of vitamin B12 is known as methylcobalamin which is required for methylation.
But, in people who are deficient in methyl groups, methyl B12 supplements are given that provide these crucial methyl groups for the process of methylation.
What does methyl B complex do?
Methyl B complex is a vitamin B supplement that contains 8 essential B vitamins, choline, inositol, and folate.
Vitamin B is needed by the body to convert food into energy and the methyl B complex enables the body to do so in individuals who have a deficiency of the same.
What is N methylation?
In N methylation, the methyl group is attached to the Nitrogen (N) atom in the substrate.
N methylation of peptides is often employed for the production of antibiotics
The structural change brought about by the addition of a methyl group to the N atom, not only helps stabilize large proteins but also inhibit actions of certain enzymes as part of a defense mechanism.
How does diet affect epigenetics?
The nutrients we eat, enter the metabolic pathways where they are modified and molded into molecules the body can use easily.
Such pathways are responsible for making methyl groups.
Nutrients like vitamin B, folic acid, etc are important parts of this methyl-making pathway.
Diets that are high in these methyl-donating nutrients rapidly affect and alter gene expression, especially very early on when the fetus is growing and the epigenome is just being established.
The food eaten by the pregnant mother shapes the epigenome of the unborn child.
Healthy methylation in the mother throughout her pregnancy ensures that her child is born healthy.
What are the factors affects your DNA?
The first thing we learn about DNA is the fact that it doesn’t change for an individual and remains the same throughout their lifetime.
However, the genes on the DNA get influenced or affected by several factors– both internal and external.
The way a gene works is known as gene expression and this can change over a period of time.
Environmental factors that affect gene expression include food, drugs exposure to chemicals and toxins. Some of these changes are inheritable.
Can diet affect DNA?
Epigenetics is the change that occurs in gene expression due to outside forces.
Epigenetics is different from mutations as epigenetics doesn’t directly affect the DNA but rather in the surroundings such as enzymes, and other chemicals that determine how a DNA molecule unwinds its various sections to make proteins and new cells.
One such factor that affects not just your DNA, but your children’s and your grandchildren's too, is diet.
Yes, what you eat affects your progeny.
If you have poor dietary habits, no matter how healthy your children or grandchildren eat, they will suffer from poor health consequences.
Diet recommendations
Over-methylation is as hazardous as under-methylation.
But, there are multiple dietary changes one can make to restore the balance of methylation.
Treat nutrient deficiencies and primarily consume adequate amounts of vitamin B12 and folate.
Apart from these, also ensure that you consume other nutrients like methionine, methionine, taurine, DHA, minerals like zinc, magnesium, potassium, and vitamins like riboflavin, niacin, choline, etc.
Maintaining a healthy gut microflora can help restore methylation and continue to maintain its efficiency.
Avoid methyl donor competitors such as environmental toxins, chronic high stress, high estrogens, high histamines, etc.
Vitamins
Individuals who suffer from MTHFR mutation must take essential nutrient supplements. Most important of them are methyl-B12, methyl folate, riboflavin, and vitamins C, D, and E.
Is DNA methylation reversible?
DNA methylation is a long-term stable conversion.
However, when the silencing of the genes must be reversed, demethylation occurs.
This is called epigenetic reprogramming.
Though the exact mechanism is not known, it has been speculated that the reprogramming or demethylation is caused by DNA deaminases that bring about the removal of amino groups.
This process of DNA demethylation occurs in all mammalian systems in all genomes.
Does DNA methylation increase with age?
DNA methylation is said to increase with age.
As one is aging, the DNA methyltransferases or DNMTs start the methylation process more frequently in some cytosine-rich areas.
These areas are non-coding areas that contain no genetic information and are located ahead of the genes that will welcome the RNA polymerase enzyme that is responsible for the transcription.
When the promoters get hyper-methylated, the RNA polymerase cannot hook up onto them and this inhibits gene transcription.
What is the purpose of DNA methylation and histone modification?
DNA methylation is an essential part of the human and mammalian genome.
Hyper or hypo-methylation has negative effects on the body.
In fact, DNA methylation and histone modification are said to be responsible for the development of neurodegenerative diseases like Alzheimer’s and Parkinson’s.
Can Mthfr cause high blood pressure?
Studies in recent times have shown that the folate metabolizing enzyme MTHFR is among the 8 loci that have been associated with blood pressure.
677C ->T polymorphism of MTHFR is said to increase the risk of hypertension by 24-78% and cardiovascular diseases by up to 40%.
MTHFR and other related conditions
DNA methylation influences the onset and progression of many disease conditions because it acts as an effector of many of environmental factors such as diet and lifestyle both of which influence the development of cardiovascular diseases.
Analyze your DNA raw data for your MTHFR gene profile
References
- https://en.m.wikipedia.org/wiki/Methylenetetrahydrofolate_reductase_deficiency
- https://ghr.nlm.nih.gov/gene/MTHFR
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521964/
- https://www.nature.com/scitable/topicpage/the-role-of-methylation-in-gene-expression-1070
- https://www.hhmi.org/research/reversible-rna-and-dna-methylation
- https://www.sciencedirect.com/science/article/pii/S0047637417302671
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156363/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156363/
- https://www.ncbi.nlm.nih.gov/pubmed/27720779
- https://www.ncbi.nlm.nih.gov/pubmed/25091541
Xcode Life's MTHFR and Methylation Report gives you the status of more than 15 genes associated with the methylation pathway.
