DNA methylation dynamic in male rat germ cells during gametogenesis

Abstract

In mammals, a near complete resetting of DNA methylation (DNAme) is observed during germline establishment. This wave of epigenetic reprogramming is sensitive to the environment which could impair the establishment of an optimal state of the gametes’ epigenome, hence proper embryo development. Yet, we lack a comprehensive understanding of DNAme dynamics during spermatogenesis, especially in rats, the model of choice for toxicological studies. Using a combination of cell sorting and DNA methyl-seq capture, we generated a stage-specific mapping of DNAme in 9 populations of differentiating germ cells from perinatal life to spermiogenesis. DNAme was found to reach its lowest level at gestational day 18, the last demethylated coding regions being associated with negative regulation of cell movement. The following de novo DNAme displayed three different kinetics with common and distinct genomic enrichments, suggesting a non-random process. DNAme variations were also detected at key steps of chromatin remodeling during spermiogenesis, revealing potential sensitivity. These methylome datasets for coding sequences during normal spermatogenesis in rat provide an essential reference for studying epigenetic-related effects of disease or environmental factors on the male germline.

Genome-wide DNA methylation changes in human spermatogenesis

“…These regions correspond to genes specifically expressed by spermatids. Our hypothesis is further corroborated by analogous results in rodents, which demonstrate that the spermatid methylome undergoes differential methylation during spermiogenesis and is enriched for regulatory binding sites when compared to spermatogonial stem cells (Kubo et al , 2015; El Omri-Charai et al , 2023).…”

“…The establishment of the germ cell methylome extends beyond prenatal development (Oakes et al , 2007; Langenstroth-Röwer et al , 2017; Di Persio et al , 2021a; El Omri-Charai et al , 2023; Huang et al , 2023). In this study, we used whole methylome sequencing of germ cells to identify changes in DNA methylation occurring during human spermatogenesis.…”

“…There is growing evidence that the establishment of the male germ cell methylome is not restricted to embryonic development, but continues in adulthood during spermatogenesis (Oakes et al , 2007; Langenstroth-Röwer et al , 2017; Di Persio et al , 2021a; El Omri-Charai et al , 2023; Huang et al , 2023). Especially in the early phases of meiosis, when replication and recombination occur, the genome is hypomethylated.…”

Mechanistic target of rapamycin (mTOR) pathway in Sertoli cells regulates age-dependent changes in sperm DNA methylation

“…Global methylation drop of around 12-13% occurs in preleptotene spermatocytes and methylation is gradually reestablished during leptotene-pachytene stages so that the final DNA methylation patterns are obtained by the end of pachytene spermatocyte stage (Gaysinskaya et al, 2018 ;Loukinov et al, 2002 ;Oakes et al, 2007 ). A recent rat study identified the transition from elongating spermatids to late spermatids as another stage associated with changes in methylation of more than 5,000 DNA regions (Omri-Charai et al, 2023 ). After fertilization, most parental-specific epigenetic marks of gametes undergo reprogramming to establish totipotency in the developing embryo.…”

Genome-wide DNA methylation changes in human spermatogenesis

“…There is growing evidence that the establishment of the male germ cell methylome is not restricted to embryonic development but continues in adulthood during spermatogenesis. 1 , 2 , 3 , 4 , 5 Especially in the early phases of meiosis, when replication and recombination occur, the genome is hypomethylated. This event is highly conserved between mouse and human and has been hypothesized to result from a delay in DNA methylation maintenance.…”