Epigenetic dysregulation in recurrent pregnancy loss: the pivotal roles of DNMT and TET enzymes

Abstract Recurrent pregnancy loss (RPL), defined as two or more consecutive miscarriages, poses significant challenges in reproductive medicine due to its multifactorial etiology, including genetic, immunologic, and environmental factors. Emerging evidence highlights the critical role of epigenetic modifications, particularly DNA methylation, in RPL. This review explores the involvement of DNA methyltransferase (DNMT1, DNMT3A, DNMT3B) and ten-eleven translocation (TET1, TET2, TET3) enzymes in regulating embryonic and placental development. Dysregulation of these enzymes disrupts the balance between methylation and demethylation, leading to aberrant gene expression and increased miscarriage risk. In recurrent pregnancy loss, excessive oxidative stress and disrupted metabolic homeostasis can impair the enzymatic machinery maintaining DNA methylation turnover. DNMT downregulation has been associated with depleted cellular levels of S-adenosylmethionine (SAM), the principal methyl donor, whereas reduced TET activity may result from an imbalance in α-ketoglutarate (αKG) and Fe²⁺ availability cofactors required for 5-methylcytosine oxidation. These conditions collectively attenuate methylation-demethylation dynamics and contribute to aberrant epigenetic programming in trophoblast and decidual tissues. Studies demonstrate altered DNMT and TET expression in chorionic and decidual tissues of RPL patients, correlating with global hypomethylation or hypermethylation of key developmental genes. Genetic polymorphisms in DNMT and TET genes further elevate RPL susceptibility. Diagnostic approaches, including RT-qPCR, bisulfite sequencing, and methylation microarrays, enable precise assessment of epigenetic profiles, offering potential biomarkers for early risk prediction. Therapeutically, DNMT inhibitors like 5-azacytidine, TET activators such as vitamin C, and emerging CRISPR-based epigenetic editing present promising avenues for restoring epigenetic balance, though challenges like safety and specificity remain.