DNA Methylation: A Key Regulator in Male and Female Reproductive Outcomes

Abstract

DNA methylation is a well-studied epigenetic modification that regulates gene expression, maintains genome integrity, and influences cell fate. It is strictly regulated by a group of enzymes known as DNA methyltransferases (DNMTs). Most DNA methylation occurs at cytosines within symmetrical CpG dinucleotide base pairs, often located at gene promoters or other regulatory elements. Thus, methylation of a promoter CpG island leads to stable transcriptional repression of the associated gene. Nonetheless, abnormal gene expression caused by alterations in DNA methylation has been linked to infertility in both males and females, as well as to reproductive potential and improper post-fertilization embryo development. Recent epigenetic advancements have highlighted the significant association between epigenetic modification and reproductive health outcomes, garnering considerable attention. In this review, we explore significant advancements in understanding DNA methylation, emphasizing its establishment, maintenance, and functions in male and female reproductive sex cells. We also shed light on the recent discoveries on the influence of environmental exposures, nutrition, infection, stress, and lifestyle choices on DNA methylation. Finally, we discuss the latest insights and future directions concerning the diverse functions of DNA methylation in reproductive outcomes.

Keywords: DNA methylation; age; epigenetic modification; infection; lifestyle; obesity; reproductive health; steroids; stress.

Figure 1

Functional roles of DNA methylation during gametogenesis and early embryonic development. DNA methylation, catalyzed DNMTs, modulates chromatin structure by promoting the transition between active (open) and repressive (closed) states. This schematic illustrates how methylation-dependent chromatin remodeling coordinates essential developmental processes, including transcriptional regulation, transposable element silencing, genomic imprinting, X-chromosome inactivation, and lineage specification. Arrows emerging from open chromatin denote processes that require transcriptional accessibility, whereas those from closed chromatin indicate pathways reliant on gene silencing. Together, these mechanisms underpin genome stability, reproductive fitness, and the faithful transmission of epigenetic information.

Figure 2

The role of infection in modulating DNA methylation.