Methylation

Overview

Methylation is the addition of a methyl group (-CH₃) to DNA, histones, proteins, or small molecules. DNA methylation (at CpG sites) is the primary epigenetic mechanism silencing gene expression, and it requires the methyl donor S-adenosylmethionine (SAMe), which depends on the methionine cycle — itself dependent on B12, folate, and homocysteine metabolism. The gut microbiome produces B12 and folate, making it a direct regulator of the host's methylation capacity.

Metal-Methylation Interface

  • Arsenic: Arsenite is methylated by arsenite methyltransferase (AS3MT) using SAMe as methyl donor. Chronic arsenic exposure depletes SAMe pools, causing genome-wide hypomethylation → aberrant gene activation → carcinogenesis [1].
  • Nickel: Induces DNA hypermethylation at tumor suppressor gene promoters, silencing their expression → carcinogenesis [2].
  • Cadmium: Disrupts DNA methyltransferase activity, causing both hypo- and hypermethylation.

Microbiome Connection

  • Gut bacteria produce B12 and folate — essential cofactors for methionine synthase (converts homocysteine → methionine → SAMe). Dysbiosis-driven loss of B-vitamin producers reduces methylation capacity.
  • Hashimoto's: Altered methylation profiles linked to microbiome-metabolome interactions [3].
  • CRC: Aberrant methylation of tumor suppressors driven by microbiome-metabolome crosstalk [4].

Cross-References

References (4)

  1. Konstantin Salnikov, Anatoly Zhitkovich (2008). Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and Cocarcinogenesis: Nickel, Arsenic, and Chromium. Chemical Research in Toxicology. doi:10.1021/tx700198a
  2. Genchi G, Carocci A, Lauria G et al. (2020). Genchi 2020 — Nickel: Human Health and Environmental Toxicology. International Journal of Environmental Research and Public Health. doi:10.3390/ijerph17030679
  3. Sarandi E, Tsoukalas D, Rudofsky G et al. (2025). Identifying the metabolic profile of Hashimoto's thyroiditis from the METHAP clinical study. Scientific Reports. doi:10.1038/s41598-025-89600-1
  4. Loke MF, Chua EG, Gan HM et al. (2018). Metabolomics and 16S rRNA Sequencing of Human Colorectal Cancers and Adjacent Mucosa. PLOS ONE. doi:10.1371/journal.pone.0208584

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