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 salnikov 2008 metal carcinogenesis.
- Nickel: Induces DNA hypermethylation at tumor suppressor gene promoters, silencing their expression → carcinogenesis genchi 2020 nickel human health environmental toxicology.
- 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 sarandi 2025 metabolic profile hashimotos methap.
- CRC: Aberrant methylation of tumor suppressors driven by microbiome-metabolome crosstalk loke 2018 metabolomics 16s crc mucosa.
Cross-References
- vitamin b12 — essential cofactor for methionine synthase
- homocysteine — methylation cycle intermediate
- arsenic — SAMe-depleting methylation
- nickel — epigenetic gene silencing via hypermethylation
- epigenetic modifications — broader epigenetic context