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Journal 6 min read

What is DNA methylation?

DNA methylation is the covalent addition of a methyl group to cytosine, typically at CpG dinucleotides, forming 5-methylcytosine. This page summarises research on its measurement, its role in gene regulation, and its stu

peptides-pro Editorial

What is DNA methylation?

DNA methylation is the covalent transfer of a methyl group to the carbon-5 position of cytosine, most often within CpG dinucleotides, yielding 5-methylcytosine (5mC). It is a principal epigenetic mark: it does not alter the underlying sequence but is copied through cell division and can change gene transcription. Synonyms in the literature include cytosine methylation, CpG methylation, and 5mC. The methyl donor in the reaction is S-adenosyl-L-methionine (SAM), and the enzymes that write the mark are the DNA methyltransferases (DNMT1, DNMT3A, DNMT3B). The mark is read by methyl-CpG-binding domain (MBD) proteins and can be removed by ten-eleven translocation (TET) enzymes. In the evidence reviewed here, DNA methylation is measured by bisulfite sequencing, methylation arrays, or methylome datasets, and is reported as a proportion of methylated cytosines at defined CpG sites.

The work summarised on this page centres on the DNMT enzyme family and on the TET-mediated demethylation pathway, with additional studies of the interferon gamma (IFNG) promoter, the vasoactive intestinal peptide receptor 2 (VIPR2) gene, and the insulin-like growth factor 1 (IGF1)/growth hormone (GH) axis.

Research Studies

DNA methylation and partial reprogramming in mammalian tissues

An integrative secondary analysis pooled five publicly available DNA methylation datasets from partial reprogramming experiments. The datasets spanned multiple mammalian species, tissues, cell types, and combinations of Yamanaka factors. The authors reported conserved partial reprogramming effects on the methylome, supporting the view that DNA methylation patterns are a targetable component of biological decline in the models examined [2].

IFNG promoter methylation and viral load in people with HIV

In people with HIV (PWH), DNA methylation at the IFNG promoter was quantified by bisulfite sequencing in peripheral blood mononuclear cells (PBMCs). Participants were grouped by plasma HIV RNA: high (n = 16; >5000 copies/µL), medium (n = 18; 500 to 4999 copies/µL), or undetectable (n = 18; ≤50 copies/µL). Differential CpG methylation in the IFNG promoter correlated with viral load and with transcriptional control of IFNG mRNA [5].

Vipr2 methylation and expression in a rat ADHD model

In spontaneous hypertensive rats (SHRs), an animal model of ADHD, researchers examined mRNA expression and DNA methylation levels of the Vipr2 gene in the prefrontal cortex, nucleus accumbens, and other brain regions. Vipr2 gene expression was upregulated in the nucleus accumbens during early life. The study was designed to test whether brain Vipr2 methylation and expression relate to prior peripheral findings in ADHD [6].

DNA methylation and glucose metabolism in chronic low back pain

A registered clinical study (NCT07734714) aims to examine whether DNA methylation and functional protein levels predict postprandial glycemic responses to standardized drinks, standardized meals, and real-life meals in patients with chronic low back pain (CLBP). The project builds on findings that impaired glucose metabolism is a comorbidity of CLBP and that the IGF1/GH axis participates in pain modulation [4].

Natural compounds as epigenetic modulators in gynaecological cancers

A review synthesised evidence on epigenetic alterations in ovarian, cervical, and endometrial malignancies, including aberrant DNA methylation, altered histone modifications, dysregulated non-coding RNAs, and m6A RNA remodelling. The authors evaluated dietary and natural compounds as epigenetic modulators and identified a knowledge gap: direct evidence that natural compounds modulate m6A machinery in gynaecological cancers remains absent [3].

Polyphenols and epigenetic regulation in neurodegenerative diseases

A review examined epigenetic regulation in neurodegenerative diseases, including DNA methylation, histone modifications, and non-coding RNA regulation. It assessed natural polyphenolic compounds as candidate neuroprotective interventions, noting their multi-target properties and the role of epigenetic mechanisms in disease onset and progression [8].

Hederagenin and DNMT1-mediated Klotho methylation in diabetic kidney disease

Hederagenin is a naturally occurring pentacyclic triterpenoid found in several medicinal plants traditionally used for renal and metabolic disorders. A study investigated its ability to attenuate renal senescence in diabetic kidney disease (DKD) and the associated epigenetic mechanisms, focusing on DNMT1-mediated Klotho DNA methylation [9].

Piperlongumine derivatives and DNMT3A-mediated methylation in prostate cancer

Fourteen novel 1,2,3-triazole-hybridized piperlongumine derivatives were synthesised through rational structural modification. In prostate cancer models, the compounds were reported to exert multimodal antitumor effects via MAPK pathway activation, poly-mechanistic apoptosis induction, and DNMT3A-mediated DNA methylation reduction [11].

DNA methylation in Prader-Willi syndrome and diabetes

A case report described an adult female with Prader-Willi syndrome (PWS) and diabetes mellitus. PWS results from loss of expression of paternally inherited genes in the 15q11.2-q13 region and is characterised by severe hypotonia and feeding difficulties in infancy, followed by hyperphagia in later childhood and adolescence, which can lead to severe obesity and type 2 diabetes mellitus. The report described tirzepatide-responsive refractory diabetes mellitus in this patient [1].

DNA methylation in polycystic ovary syndrome and type 1 diabetes

A cross-sectional comparative clinical study (NCT07490964) was designed to investigate pathogenic mechanisms behind functional hyperandrogenism in women with type 1 diabetes (T1D), including polycystic ovary syndrome (PCOS). The hypothesis is that individual factors expose or protect women with T1D to androgen excess and PCOS, and that such androgen excess may increase cardiometabolic risk. The study includes five groups of subjects and takes a sex/gender-medicine and sexual dimorphism perspective [7].

Extracellular matrix and microvascularization genes in the mare placenta

In the mare placenta, a study evaluated gene transcription and expression of enzymes regulating collagen deposition (matrix metalloproteinases MMP2 and MMP9) and their inhibitors (TIMP1 and others), alongside microvascularization regulatory genes. The work addresses molecular mechanisms of extracellular matrix collagen deposition and vascularization in this tissue [10].

sORF-encoded microproteins as emerging regulators

The human genome contains hundreds of thousands of short open reading frames (sORFs). Their translational products, termed sORF-encoded microproteins (historically micropeptides), have long been overlooked in conventional genome annotation. Increasing evidence demonstrates that these microproteins have regulatory roles in human physiology and disease [12].

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