What Is Demethylation?

Understanding DNA demethylation can help to clarify how the methylation cycle works and where problems might arise.

MTHFR (methylenetetrahydrofolate reductase) is an enzyme that helps produce methyl groups by converting folate into its active form, methylfolate. Methylfolate then assists in converting homocysteine to methionine, and methionine is used to create SAMe (S-adenosylmethionine) - the body’s main methyl donor.

The methylation process is required for regulating gene expression (via DNA methylation), neurotransmitter production, hormone metabolism, boosting glutathione and many other vital functions. An MTHFR mutation can impair the methylation process, potentially leading to imbalances across many systems.

No, demethylation is not directly related to MTHFR. While MTHFR is involved in producing methyl groups required for the body’s methylation processes, demethylation refers to the removal of those methyl groups (particularly from DNA). This controls whether a gene is used or not.

MTHFR is not involved in the removal process, and a lack of methylfolate does not cause demethylation.

While methylation adds a methyl group to DNA (usually to repress gene activity), demethylation removes it, allowing genes to be reactivated.¹

Specifically, demethylation is the biochemical process of removing a methyl group (–CH₃) from a molecule. In DNA demethylation, methyl groups are removed from 5-methylcytosine (5mC), the methylated form of cytosine (one of the four bases of DNA).

DNA methylation and demethylation are like on/off switches for genes. This is part of epigenetic regulation, which is how your body controls which genes are active without changing the actual DNA code.

Methylation "marks" genes in a way that typically makes them less likely to be expressed (used). Demethylation removes those marks, allowing those genes to be activated again. In this way, demethylation helps to control which genes are used and when.

In Alzheimer’s patients, for example, abnormal methylation patterns in the APOE gene can reduce its ability to clear amyloid plaques in the brain, which is a key feature of the disease. Demethylating the APOE gene - that is, removing the methyl groups that silence it - could potentially reactivate it, improving its plaque-clearing function and possibly slowing disease progression. Reduced DNA methylation in the APOE gene region, however, has been linked to decreased cognitive performance.

This system helps your body:

• Turn off one of the X chromosomes in females (so it doesn't double the dose of X-linked genes)
• Make sure certain genes are only active if inherited from one parent (this is called imprinting)
• Keep potentially harmful “jumping genes” quiet, so they don’t alter DNA

Demethylation techniques are methods used in medical research to remove methyl groups from DNA. These have been investigated in relation to cancer treatment and gene expression.

Targeted (gene-specific) DNA demethylation techniques are emerging as a promising solution for treating diseases caused by specific epigenetic changes. This involves reactivating specific silenced genes by removing methylation at precise locations.² These gene-specific demethylation tools may be a new kind of therapy for epigenetically driven diseases, such as cancer (where abnormal methylation/demethylation silences tumor suppressor genes), neurodevelopmental conditions (e.g., Rett syndrome).