What is DNA Hypermethylation?

What is DNA Hypermethylation?

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - Bachelor of Science in Nursing

Medical Reviewer:

Kari Asadorian - Bachelor of Science in Nursing
Jamie Hope - Founder of Methyl-Life

Edited By:

Jamie Hope - Founder of Methyl-Life

Updated On:

June 10, 2025

Table of Contents

    Understanding hypermethylation can help you to understand how genes can be turned off in ways that increase the risk of certain diseases, including dementia, cancer, and other age-related conditions.

    What is hypermethylation?

    Hypermethylation is an abnormal form of methylation. It occurs when too many methyl groups are added to DNA, mainly at CpG sites - regions where biochemical switches can be added to control whether certain genes are turned on or off.1
    CpG sites play a key role in DNA methylation, the process that regulates whether genes are expressed or silenced. Hypermethylation can result in gene silencing (the turning ‘off’ of a gene).

    Effects of hypermethylation

    Hypermethylation can interfere with healthy cellular function in several ways:


    • Silencing (suppressing or limiting) of certain genes
      This can decrease the expression of the gene and the proteins it is supposed to produce.
      In some cases, nearby non-coding RNA genes can also be affected, potentially causing broader alterations across more genes.
      For example, hypermethylation of the BRCA1 promoter region leads to reduced expression of the gene, which has been observed in some cancers (breast and ovarian).2
    • 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. Chromatin structure can be affected, impacting how the DNA loops and interacts, and altering histone modifications.
    • Increase risk of disease
      Hypermethylation is seen in some neurological disorders and aging-related conditions.3
      In the general population, methylation levels generally decrease with age. However, in individuals with Alzheimer’s disease, researchers have found that methylation of certain genes (including MTHFR and APOE) increased.4 APOE helps to remove amyloid plaques from the brain, and MTHFR and DNMT1 are involved in methylation and gene regulation. The altered methylation patterns may therefore contribute to disease development or progression.


    In short, hypermethylation can silence critical genes, including those required for preventing chronic illness. This can increase the risk of harmful cells growing out of control.

    What causes hypermethylation?

    Hypermethylation can occur due to a combination of factors, including changes in the enzymes responsible for methylation, environmental influences, aging processes, and specific health conditions.


    • Dysregulation of DNA Methyltransferases (DNMTs)
      Mutations in DNMT genes, such as DNMT3A and DNMT3B, can disrupt their function, leading to altered DNA methylation patterns. For example, mutations in DNMT3A have been linked to developmental disorders and certain cancers, such as acute myeloid leukemia.5
      DNMTs are enzymes that control methylation by catalyzing the addition of a methyl group to the 5th position of cytosine residues in DNA. Increased or altered DNMT activity can result in excessive methylation at specific gene sites.6
    • Environmental factors
      Chronic exposure to environmental chemicals, including air pollutants and tobacco smoke, can lead to methylation changes.7
    • Diet
      Poor diet and nutritional deficiencies can impact developmental programming and influence DNA methylation. A high-methionine diet can lead to increased levels of SAMe and greater global hypermethylation, which then causes gene silencing and produces high levels of homocysteine.8 Homocysteine is a compound associated with inflammation and damage to both cardiovascular and cognitive function.
    • Aging and oxidative stress
      Age-related hypermethylation is linked to alterations in DNMT expression, such as downregulation of DNMT1 and overexpression of DNMT3B. This can contribute to both hypomethylation and hypermethylation in different regions of DNA. Tumor suppressor genes are commonly affected by age-related hypermethylation.9

    Symptoms of hypermethylation

    While DNA hypermethylation refers to gene regulation, it is often confused with excessive intake of methyl donors through supplements or diet, which may produce different physiological effects. Please note that these are two distinctly different aspects of genetics and nutrition.


    • Hypermethylation typically refers to gene silencing (as explained above), which can lead to certain genes being ‘turned off’, such as tumor suppressor genes in cancer.
    • A high methyl diet (or taking excess methyl donors e.g., methylated B12 and methylfolate) can impact neurotransmitters, which may lead to acute neurological or behavioral symptoms.10 This is sometimes referred to as ‘overmethylation’.


    Animal studies suggest that excess methyl donors can increase repetitive behavior and certain hormone levels, including cortisol, estrogen, and insulin. Increased stress and anxiety has also been noted to result from excess methyl donors, as well as higher fat storage.11

    Hypermethylation and cancer

    DNA hypermethylation is a major epigenetic alteration often linked to the development of cancer. The addition of too many methyl groups can lead to the silencing of tumor suppressor genes, which help regulate cell division and prevent abnormal growth.


    However, DNA hypomethylation can also be involved in cancer. Hypomethylation occurs when too few methyl groups are added to DNA, which can lead to certain genes (including cancerous genes) being too active, as well as contributing to mutations in genes that may also lead to cancer.12

    What is DNA Hypermethylation?

    Key takeaways

    • Icon DNA hypermethylation occurs when excess methyl groups are added to DNA during the methylation process. This can lead to certain genes being turned off.
    • Icon Hypermethylation may increase the risk of cancer if tumour suppressor genes are inactivated.
    • Icon Hypermethylation may be caused by aging, diet or environmental factors

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    Frequently Asked Questions about hypermethylation

    What happens in hypermethylation?

    In hypermethylation, too many methyl groups are added to DNA, which can lead to certain genes being ‘silenced’ - i.e., inactivated. This can occur in tumor suppressor genes, which is often associated with cancer development.
    Note that hypermethylation is not the same as overmethylation, which is thought to occur due to an excess intake of methylated nutrients.

    What is the meaning of hypermethylation?

    “Hypermethylation” means an increase or excess in the methylation of DNA. Methylation is a biological process in which a methyl group is added to DNA, and this can influence gene expression.
    If hypermethylation occurs, a higher than normal level of these methyl groups are attached to the DNA, which can lead to changes in how genes are turned on or off.
    Please note that hypermethylation is not the same as overmethylation, which is associated with excess intake of methylated nutrients.

    How does hypermethylation contribute to cancer?

    Hypermethylation can cause tumor suppressor genes to be turned off, which means they play an important role in controlling cell growth. If they are turned off, certain cancer cells can grow and spread out of control. This has been noted in certain breast cancers, where hypermethylation of the BRCA1 gene is suppressed or inactivated.

    What does high methylation mean?

    High DNA methylation means that an abnormal number of methyl groups are attached to the DNA, potentially silencing key genes and disrupting normal gene regulation.

    References

    1. Xiaofan Lu, Yann-Alexandre Vano, Xiaoping Su, Alexandra Helleux, Véronique Lindner, Roger Mouawad, Jean-Philippe Spano, Morgan Rouprêt, Eva Compérat, Virginie Verkarre, Cheng-Ming Sun, Mostefa Bennamoun, Hervé Lang, Philippe Barthelemy, Wenxuan Cheng, Li Xu, Irwin Davidson, Fangrong Yan, Wolf Hervé Fridman, Catherine Sautes-Fridman, Stéphane Oudard, Gabriel G Malouf; "Silencing of genes by promoter hypermethylation shapes tumor microenvironment and resistance to immunotherapy in clear-cell renal cell carcinomas"; Cell reports. Medicine; 2023 Nov

      https://pmc.ncbi.nlm.nih.gov/articles/PMC10694769/

    2. Yassire Oubaddou, Mohamed Oukabli, Salma Fenniche, Abderrahim Elktaibi, Mohamed Reda Elochi, Abderrahmane Al Bouzidi, Zineb Qmichou, Nadia Dakka, Caroline Diorio, Antje Richter, Youssef Bakri, Rabii Ameziane El Hassani; "BRCA1 Promoter Hypermethylation in Malignant Breast Tumors and in the Histologically Normal Adjacent Tissues to the Tumors: Exploring Its Potential as a Biomarker and Its Clinical Significance in a Translational Approach"; Genes (Basel); 2023 Aug

      https://pmc.ncbi.nlm.nih.gov/articles/PMC10530732

    3. Melanie Ehrlich; "DNA hypermethylation in disease: mechanisms and clinical relevance"; Epigenetics; 2019 Jul

      https://pmc.ncbi.nlm.nih.gov/articles/PMC6791695/

    4. Samareh Younesian, Amir-Mohammad Yousefi, Majid Momeny, Seyed H Ghaffari, Davood Bashash; "The DNA Methylation in Neurological Diseases"; Cells; 2022 Oct

      https://pmc.ncbi.nlm.nih.gov/articles/PMC9657829

    5. Dae Joong Kim; "The Role of the DNA Methyltransferase Family and the Therapeutic Potential of DNMT Inhibitors in Tumor Treatment"; Curr. Oncol.; 2025

      https://www.mdpi.com/1718-7729/32/2/88

    6. Wu Zhang, Jie Xu; "DNA methyltransferases and their roles in tumorigenesis"; Open access; 2017 Jan

      https://biomarkerres.biomedcentral.com/articles/10.1186/s40364-017-0081-z

    7. Kimberly P. Keil, Pamela J. Lein; "DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders?"; Environmental Epigenetics; 2016 Jan

      https://academic.oup.com/eep/article/2/1/dvv012/2464729

    8. Avisek Majumder, Jyotirmaya Behera, Nevena Jeremic, Suresh C Tyagi; "Hypermethylation: Causes and Consequences in Skeletal Muscle Myopathy"; Journal of cellular biochemistry; 2019 Jun

      https://pmc.ncbi.nlm.nih.gov/articles/PMC6563903/

    9. Vasily V Ashapkin, Lyudmila I Kutueva, Boris F Vanyushin; "Aging as an Epigenetic Phenomenon"; Current genomics; 2017 Oct

      https://pmc.ncbi.nlm.nih.gov/articles/PMC5635645/

    10. Nicole Yadon, Amy Owen, Patricia Cakora, Angela Bustamante, April Hall-South, Nuri Smith, Michael R Felder, Paul B Vrana, Kimberly R Shorter; "A high methyl donor diet affects physiology and behavior in Peromyscus polionotus"; Physiology & behavior; 2019 Oct

      https://pubmed.ncbi.nlm.nih.gov/31299371/

    11. Nicole Yadon, Amy Owen, Patricia Cakora, Angela Bustamante, April Hall-South, Nuri Smith, Michael R Felder, Paul B Vrana, Kimberly R Shorter; "A high methyl donor diet affects physiology and behavior in Peromyscus polionotus"; Physiology & behavior; 2019 Oct

      https://pubmed.ncbi.nlm.nih.gov/31299371/

    12. Marta Kulis, Manel Esteller; "DNA methylation and cancer"; Advances in genetics; 2010

      https://pubmed.ncbi.nlm.nih.gov/20920744

    Katie Stone - Naturopath

    About the Author

    Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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