Fig. 6: The global DNA methylation process throughout the paternal life cycle.

The human spermatogenesis process begins at puberty, with each cycle lasting approximately 64 days. Following fertilisation genome-wide DNA demethylation occurs within the zygote, with the exception of epigenetically inherited imprints. Progressive demethylation continues until the blastocyst stage, when DNA methylation levels are at their lowest just prior to implantation. DNA methylation patterns are then re-established following implantation. A second round of DNA demethylation that includes the demethylation of epigenetically inherited imprints occurs in primordial germ cells at the end of trimester 1, where they now have the least methylated genome of the entire lifespan. However, epigenetically inherited imprints are protected by an unknown mechanism from this second round of genome-wide demethylation [155, 156]. Following the second round of DNA demethylation, DNA re-methylation occurs, which continues into the post-natal development stages. Figure was created with BioRender.com.