DNA methylation is an essential process controlling how your genetic information is used by the cells in your body. This complex biochemical process literally turns on and off genes, and assists with cellular repair.
It is a key process in epigenetics (lifestyle’s impact on genetics), along with histone modification and non-coding RNA -associated gene silencing.
Quite a mouthful, huh?
Your cells are methylating right now as you read this.
What is DNA methylation?
Each cell turns on, or expresses, only some of its genes some of the time, and DNA methylation is one of the main ways in which gene activity is regulated without changing the sequence of your DNA.
Several diseases and disorders have been connected to abnormal methylation of DNA.
Because too much methylation (hypermethylation) or too little (hypomethylation) can lead to improper gene expression and abnormal cell activity.
For example, consider tumor suppressor genes, which are genes used by the body to suppress unregulated cell division (AKA cancer). If a tumor suppressor gene becomes hypermethylated (i.e. over-methylated) and isn’t expressed, cells may be more likely to proliferate and become cancerous.
Conversely, hypomethylation (i.e. under-methylation) of a gene that promotes cell division means more expression of that gene and a greater degree of rapid uncontrolled cell growth. As you can see, our bodies are finely balanced and any imbalance can have profound effects on our health and wellbeing.
Such modifications can be inherited and are often influenced by extrinsic (environmental) factors, specifically at the time of conception and during the gestation period 1.
But what is DNA methylation?
The simplest definition is that DNA methylation is a biological process where methyl groups are added to strands of DNA. These methyl groups enable the key processes of DNA transcription, replication, and repair, as well as others. And these processes themselves ensure that cells grow, divide, and replicate properly.
To appreciate what might go wrong with DNA methylation, we need to know a bit more about how it works. Without getting into the weeds too much, these are the main steps involved in DNA methylation:
- Enzymes known as DNA methyltransferases (DNMTs) bind to DNA.
- S-adenosylmethionine (SAM) is recruited as a methyl group donor
- DNMT enzymes incorporate the methyl group from SAM into carbon 5 of the cytosine residue
- The DNMT enzyme is released along with a s-adenosylhomocysteine (SAH) molecule.
As you can see above, DNA methyltransferase (DNMT) enzymes facilitate the transfer of the methyl group, from SAM to DNA. This means that anything which affects DNMT enzymes can also affect DNA methylation and normal cellular growth, replication, and division.
S-adenosylmethionine (SAM), a co-factor and universal methyl donor for DNMT, is created from methionine, an amino acid. After SAM donates its methyl group to DNA, it becomes s-adenosylhomocysteine (SAH), a compound incorporating another amino acid called homocysteine (see Cardiovascular disease and DNA methylation).
Importantly, methionine can be renewed by the transfer of a methyl group to homocysteine from N5-methyltetrahydrofolate. In animals, including humans, this reaction requires the enzyme methionine synthase (MS) which itself requires vitamin B12 as a co-factor. Tetrahydrofolate – a form of the B vitamin folate – is also involved in transporting methyl groups. (More on this below.)
Where does DNA methylation occur?
You already know that DNA is found in every cell in your body, but where does methylation happen in DNA?
Remember how DNA is made up of T, G, A, and C bases? Well, methylation of DNA happens at the fifth position of cytosine (C) when it is beside a guanine (G) nucleotide. This is commonly referred to as symmetric cytidine-guanine dinucleotide, or CpG (see Figure 2).
Figure 2. Methylation of DNA. Figure adapted from Stevens et al., 2018 2. (Abbreviation: DNMT: DNA methyltransferase, SAM: S-adenosylmethionine, SAH: S-adenosylhomocysteine)
Methylation occurs at approximately 70-80% of CpG sites throughout the genome 3. An individual’s DNA sequence can also affect the level of methylation in the CpG nucleotides. This can be seen thanks to single nucleotide polymorphisms (SNPs) present in the regions near to these sites. For example, if one of those C nucleotides is replaced with another nucleotide, then that region of DNA will not be able to be methylated; if a CpG pair is created, however, then methylation may become possible.
When does DNA methylation happen?
There are specific, well-defined stages in our lives when precise, regulated, and predictable genome-wide patterns of DNA methylation occur. These changes are crucial for the control of tissue-specific gene expression and play a major role in influencing the phenotypic development.
X-inactivation is an example of a really interesting process controlled by DNA methylation. Although it’s not always the case (some people have three chromosomes, for example), most male humans have an X and a Y sex chromosome, whereas most females have two copies of the X chromosome. This means that most males have one copy of all the genes on the X chromosome, whereas females have two copies. Therefore, if both X chromosomes remained active in females, they would have nearly twice the level of expression of those genes compared to males. To prevent this ‘overexpression’, one X chromosome is inactivated in females. This inactivation occurs early in development and is random. Once inactivated, that specific chromosome will remain inactive throughout an individual’s lifetime.
In addition, the DNA methylation pattern acquired during early embryonic development is also now known to be maintained throughout later life 4. This process is called genomic imprinting.
These patterns are maintained by various biochemical pathways, including the one-carbon cycle, and associated enzymes, such as DNA methyltransferases.
What affects DNA methylation?
As mentioned above, DNA methylation can be affected by a range of extrinsic (environmental) factors. Diet is among one of the most important environmental factors that can not only influence the process of genomic imprinting but induce alterations in the methylation patterns which keep on changing throughout adulthood.
Several dietary components have now been shown to influence DNA methylation in animal models as well as experimental studies.
For instance, vitamins B2 (riboflavin) and B6 (pyridoxine) are involved in DNA methylation as co-factors for enzymes including methylenetetrahydrofolate reductase (MTHFR) and serine hydroxymethyltransferase (SHMT).
Betaine is also an important methyl donor and can be produced from choline, a nutrient often grouped together with B vitamins because of these overlapping roles in metabolism.
See also: Key Nutrients Impacting DNA Methylation
As you’d expect, any deficiencies or other issues with these co-factors or enzymes can change the activity of folate and the methionine cycle, which would then affect DNA methylation.