What Is DNA Hypomethylation?

To understand hypomethylation, you first need to understand DNA and methylation.

DNA is like a long instruction book for the body, with genes as different chapters. Some regions of DNA contain a lot of CpG sites, where the letters C and G (cytosine and guanine) appear together frequently. These areas (called CpG islands) are often found near genes and help regulate their activity.

Methylation is the process of adding small chemical groups (methyl groups) to DNA, usually at CpG sites. This helps control which genes are turned on or off at the right time.

For methylation to happen, your body needs a methyl group - a molecule made up of carbon and hydrogen. Methylfolate, the active form of folate, provides this methyl group. This group is added to certain parts of DNA to turn genes on or off.

Methylation usually silences genes, but in some cases, it helps activate them. The effect depends on the gene and its function.¹

Hypomethylation occurs when too few methyl groups are added to DNA. This can lead to genes being too active when they should be controlled. Instead of affecting just one gene, hypomethylation can cause widespread changes across the genome, leading to chromosomal instability and the reactivation of dormant DNA elements (such as transposable elements).

Transposable elements are pieces of DNA that can move around the genome. While some transposable elements have neutral or even beneficial effects, they can sometimes disrupt important genes.²

Genome instability is a high frequency of mutations within the genome (the entire set of DNA instructions in a cell) of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements, or aneuploidy.³

Hypomethylating agents (HMA) are a class of drugs that reverse abnormal DNA methylation.⁴

In simple terms, they are used to counteract the excessive methylation of certain genes, particularly tumor suppressor genes, allowing them to function properly again.

For example, some cancers turn off important genes that normally control cell growth, allowing tumors to grow unchecked. By reversing this process, HMAs help to re-activate silenced tumor suppressor genes, potentially slowing the progression of a disease.

The most common HMAs are azacitidine and decitabine, which are used to treat blood cancers like myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), especially in older patients. However, over time, cancer can become resistant to these drugs, so new treatments and drug combinations are being developed.

As explained above, DNA methylation is like a control system for genes: it helps decide which genes should be active and which should stay off. When methylation is balanced, genes turn on and off at the right times. But when methylation goes wrong, it can lead to disease.

Hypomethylation means too few methyl groups are added to DNA. This can cause:

• Overactive genes: Some genes that should be controlled stay switched on.
• Genomic instability: The loss of proper methylation can weaken chromosome structure, leading to errors in DNA.
• Activation of ‘jumping genes’: Normally silent pieces of DNA (transposable elements) can start moving around, potentially disrupting important genes.
• Possible risk of cancer:  Hypomethylation is often seen in cancer cells, where it contributes to uncontrolled growth and genetic damage.

Hypermethylation is the opposite: too many methyl groups are added. This can lead to:

• Silencing of important genes, including tumor suppressor genes, which help prevent cancer.
• Disruption of normal cell function: If key regulatory genes are switched off, cells may grow out of control or lose their ability to repair damage.
• Increase risk of disease: Hypermethylation is seen in some neurological disorders and aging-related conditions.⁵

In short, hypomethylation can lead to overactive genes, loss of genetic stability, and increased mutation rates. Hypermethylation, on the other hand, can silence critical genes, including tumor suppressors, which increases the risk of uncontrolled cell growth.

Cancer-related DNA hypomethylation is as common as hypermethylation but affects different parts of the genome.

Hypermethylation silences protective tumor suppressor genes but hypomethylation removes the ‘brakes’ on cell growth. This can mean cancer cells become more aggressive, increasing their ability to invade other tissues.

Hypermethylation mainly occurs in CpG islands within gene regions, while hypomethylation can occur across many segments of DNA. This undermethylation may contribute to cancer by increasing genomic instability and activating tumor-promoting genes. Research suggests that although reducing DNA methylation can have short-term anticancer effects, it may also accelerate tumor progression in surviving cancer cells.⁶

Too little methylation across the genome can lead to overactive genes that drive cell growth and division, potentially allowing cancer to progress faster. Hypomethylation also weakens the genome, increasing mutations and chromosomal instability. It can also reactivate the normally silent ‘jumping genes’, which destabilize DNA even further.⁷

In the case of certain cancers, DNA methylation may be increased using hypomethylating drugs, such as azacitidine and decitabine. These drugs work through multiple pathways to help reprogram tumor cells and make them ‘normal’ again, as well as sensitizing them to chemotherapy and immunotherapy.⁸

Studies have trialed treating hypomethylation with folate and folic acid, as low folate levels have been associated with decreases in global DNA methylation. In a study involving mice, supplementation prevented this loss of DNA methylation and associated inflammation.⁹

A human study found that folic acid supplementation helped restore methylation levels in folate-deprived cells. The researchers suggested that folate may have a role in supporting balanced DNA methylation.¹⁰

While research is ongoing, maintaining adequate levels of methylation-supporting nutrients (such as methylfolate and B12) may support healthy methylation patterns. However, individual methylation needs vary, so a personalized approach is highly recommended.