Deciphering DNA Methylation in Gestational Diabetes Mellitus: Epigenetic Regulation and Potential Clinical Applications

Abstract

Gestational diabetes mellitus (GDM) represents a prevalent complication during pregnancy, exerting both short-term and long-term impacts on maternal and offspring health. This review offers a comprehensive outline of DNA methylation modifications observed in various maternal and offspring tissues affected by GDM, emphasizing the intricate interplay between DNA methylation dynamics, gene expression, and the pathogenesis of GDM. Furthermore, it explores the influence of environmental pollutants, maternal nutritional supplementation, and prenatal gut microbiota on GDM development through alterations in DNA methylation profiles. Additionally, this review summarizes recent advancements in DNA methylation-based diagnostics and predictive models in early GDM detection and risk assessment for subsequent type 2 diabetes. These insights contribute significantly to our understanding of the epigenetic mechanisms underlying GDM development, thereby enhancing maternal and fetal health outcomes and advocating further efforts in this field.

Keywords: DNA methylation; epigenetics; gestational diabetes mellitus.

Figure 1

Dynamic DNA methylation and pathophysiology. DNA methylation is a reversible epigenetic mark involving the covalent transfer of a methyl group to the 5-cytosine residue by DNMTs (DNMT1, DNMT3A, DNMT3B). Methylated DNA undergoes dynamic and reversible remodeling through DNA demethylases, namely TET proteins (TET1, TET2, TET3). The dynamic DNA methylation pattern is critical for physiopathological processes such as embryonic development, aging, and cancer. C, cytosine; 5Mc, 5-methylcytosine; 5hmC, 5-hydroxymethylcytosine; 5fC, 5-formylcytosine; 5caC, 5-carboxycytosine; DNMT, DNA methyltransferase; SAM, S-adenosylmethionine; TET, ten-eleven translocation protein; MBD, DNA-binding domain.

Figure 2

DNA methylation alterations affecting GDM offspring health. Fetuses exposed to GDM present higher susceptibility to various diseases throughout their life. This may be due to the intrauterine high-glucose environment that promotes DNA methylation alterations in the offspring’s organs, affecting their biological functions.

Figure 3

Environmental factors affecting the health of GDM mother and offspring via DNA methylation. In addition to cellular differentiation regulation, DNA methylation could be a genome adaptation in response to environmental stimulations such as chemical exposure, methyl-rich diets, and intestinal microenvironment during gestation. The disturbed DNA methylation could interfere gene transcription and function to affect the health of the GDM mother and offspring.

Figure 4

DNA methylation testing in the diagnosis and risk prediction of GDM. DNA methylation testing of genome-wide or specific genes has shown potential for GDM diagnosis or risk prediction. gDNA (genomic DNA) and cfDNA are used as blood-based biomarkers, whereas general o’clock and epigenetic o’clock are placenta-based biomarkers.