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Review
. 2021 Jul 22:9:689624.
doi: 10.3389/fcell.2021.689624. eCollection 2021.

Epigenetics of Male Infertility: The Role of DNA Methylation

John Charles Rotondo  1 , Carmen Lanzillotti  1 , Chiara Mazziotta  1 , Mauro Tognon  1 , Fernanda Martini  1
Affiliations
Review

Epigenetics of Male Infertility: The Role of DNA Methylation

John Charles Rotondo et al. Front Cell Dev Biol. .

Abstract

In recent years, a number of studies focused on the role of epigenetics, including DNA methylation, in spermatogenesis and male infertility. We aimed to provide an overview of the knowledge concerning the gene and genome methylation and its regulation during spermatogenesis, specifically in the context of male infertility etiopathogenesis. Overall, the findings support the hypothesis that sperm DNA methylation is associated with sperm alterations and infertility. Several genes have been found to be differentially methylated in relation to impaired spermatogenesis and/or reproductive dysfunction. Particularly, DNA methylation defects of MEST and H19 within imprinted genes and MTHFR within non-imprinted genes have been repeatedly linked with male infertility. A deep knowledge of sperm DNA methylation status in association with reduced reproductive potential could improve the development of novel diagnostic tools for this disease. Further studies are needed to better elucidate the mechanisms affecting methylation in sperm and their impact on male infertility.

Keywords: DNA methylation; epigenomics; imprinted genes; imprinting; infertility; male infertility; sperm; sperm DNA.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The DNA methylation machinery. (A) DNA methyltranferase 3A (DNMT3A) and 3B (DNMT3B) catalyze de novo methylation reactions on cytosines belonging to CpG dinucleotides to form 5-methylcytosine. DNA methyltransferase 1 (DNMT1) mediates DNA methylation maintenance. (B) Ten-eleven translocation (TET) enzymes mediates DNA demethylation reactions.
FIGURE 2
FIGURE 2
Epigenetic reprogramming during gametogenesis. Changes of DNA methylation occur during primordial germ cell (PGC) development. During the proliferation and migration into the gonadal ridge, PGCs undergo global demethylation to remove parental imprints. Subsequently, reestablishment of the male germ cell DNA methylation patterns occurs during gametogenesis. De novo methylation occurs prior to meiosis in mitotically arrested cells while being completed before birth.
FIGURE 3
FIGURE 3
Epigenetic regulation of the imprinted IGF2-H19 gene cluster. The regulation of the imprinted genes is mediated by imprinting control regions (ICR) whose methylation regulates the imprinted genes located at the same gene cluster. On the maternal allele, at the IGF2-H19 locus, the ICR is de-methylated; this allows CTCF binding and promotes the expression of H19 and silencing of IGF2 through down-stream enhancer activity. On the paternal allele, at the IGF2-H19 locus, the ICR and H19 are methylated; this prevents CTCF binding and induces the inactivation of H19 and the expression of IGF2. Consistently, IGF2 is expressed in the sperm cell (Cannarella et al., 2019).
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