Global DNA methylation (Global DNAm)

Global DNA methylation refers to the total genomic content of 5-methylcytosine (5mC), a critical epigenetic modification that predominantly occurs at CpG dinucleotides. It plays a fundamental role in maintaining genomic integrity, regulating gene expression profiles, and governing developmental processes such as genomic imprinting and X-chromosome inactivation [1, 10]. In various pathological states, most notably cancer, the global methylation landscape is often severely disrupted; widespread genomic hypomethylation can lead to chromosomal instability and the activation of retrotransposons, while focal hypermethylation of promoter regions is a hallmark mechanism for silencing tumor suppressor genes [3, 11]. \n\nAs a therapeutic strategy, targeting the DNA methylation state involves the use of hypomethylating agents (HMAs), such as the FDA-approved drugs azacitidine and decitabine. These agents do not target the methylation marks directly but rather act as inhibitors of DNA methyltransferase (DNMT) enzymes [5, 9]. By incorporating into the DNA during the S-phase of the cell cycle, these drugs trap DNMTs, preventing the maintenance of methylation patterns in daughter cells and allowing for the re-expression of genes involved in cell cycle control and apoptosis [2, 10]. Although highly effective in hematological malignancies like myelodysplastic syndromes, the use of these drugs carries risks such as myelosuppression and the potential for off-target gene activation [6, 10].

Other names

Global methylation of genesGenome-wide DNA methylation5-methylcytosine levels5mC contentGenomic DNA methylation

Inhibition of DNA methyltransferase (DNMT) enzymes, particularly DNMT1, leading to the depletion of methyl groups during DNA replication and the subsequent reactivation of epigenetically silenced genes.