Abstract
BackgroundIn the male germline, neonatal prospermatogonia give rise to spermatogonia, which include stem cell population (undifferentiated spermatogonia) that supports continuous spermatogenesis in adults. Although the levels of DNA methyltransferases change dynamically in the neonatal and early postnatal male germ cells, detailed genome-wide DNA methylation profiles of these cells during the stem cell formation and differentiation have not been reported.ResultsTo understand the regulation of spermatogonial stem cell formation and differentiation, we examined the DNA methylation and gene expression dynamics of male mouse germ cells at the critical stages: neonatal prospermatogonia, and early postntal (day 7) undifferentiated and differentiating spermatogonia. We found large partially methylated domains similar to those found in cancer cells and placenta in all these germ cells, and high levels of non-CG methylation and 5-hydroxymethylcytosines in neonatal prospermatogonia. Although the global CG methylation levels were stable in early postnatal male germ cells, and despite the reported scarcity of differential methylation in the adult spermatogonial stem cells, we identified many regions showing stage-specific differential methylation in and around genes important for stem cell function and spermatogenesis. These regions contained binding sites for specific transcription factors including the SOX family members.ConclusionsOur findings show a distinctive and dynamic regulation of DNA methylation during spermatogonial stem cell formation and differentiation in the neonatal and early postnatal testes. Furthermore, we revealed a unique accumulation and distribution of non-CG methylation and 5hmC marks in neonatal prospermatogonia. These findings contrast with the reported scarcity of differential methylation in adult spermatogonial stem cell differentiation and represent a unique phase of male germ cell development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1833-5) contains supplementary material, which is available to authorized users.
Highlights
In the male germline, neonatal prospermatogonia give rise to spermatogonia, which include stem cell population that supports continuous spermatogenesis in adults
The genes in the Partially methylated domain (PMD) were silenced, just as were those found in cancer cells [35, 36], sharing functional features
We focused on the ~2800 Differentially methylated region (DMR) that showed reduced methylation in postnatal day 7 (P7).5 Kit− or Kit+ SGs and found that many of them are located in intergenic regions or introns, have histone marks specific for enhancers, and show association with specific gene functions such as cell proliferation, cell movement, stem cell function, and spermatogenesis
Summary
Neonatal prospermatogonia give rise to spermatogonia, which include stem cell population (undifferentiated spermatogonia) that supports continuous spermatogenesis in adults. The levels of DNA methyltransferases change dynamically in the neonatal and early postnatal male germ cells, detailed genome-wide DNA methylation profiles of these cells during the stem cell formation and differentiation have not been reported. Huge numbers of spermatozoa are produced throughout adult life This constant supply is supported by the spermatogonial stem cell (SSC) system [1,2,3]. The detailed methylation profile of neonatal PSGs has not been reported It is totally unknown how DNA methylation and gene expression profiles change during the transitions from PSGs to undifferentiated SGs and from undifferentiated to differentiating SGs in early postnatal testis
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