Centre of Reproductive Medicine and Andrology, Institute of Reproductive and Regenerative Biology, University of Münster, Münster, Germany.
Institute of Medical Informatics, University of Münster, Münster, Germany.
Am J Hum Genet. 2024 Jun 6;111(6):1125-1139. doi: 10.1016/j.ajhg.2024.04.017. Epub 2024 May 16.
Sperm production and function require the correct establishment of DNA methylation patterns in the germline. Here, we examined the genome-wide DNA methylation changes during human spermatogenesis and its alterations in disturbed spermatogenesis. We found that spermatogenesis is associated with remodeling of the methylome, comprising a global decline in DNA methylation in primary spermatocytes followed by selective remethylation, resulting in a spermatids/sperm-specific methylome. Hypomethylated regions in spermatids/sperm were enriched in specific transcription factor binding sites for DMRT and SOX family members and spermatid-specific genes. Intriguingly, while SINEs displayed differential methylation throughout spermatogenesis, LINEs appeared to be protected from changes in DNA methylation. In disturbed spermatogenesis, germ cells exhibited considerable DNA methylation changes, which were significantly enriched at transposable elements and genes involved in spermatogenesis. We detected hypomethylation in SVA and L1HS in disturbed spermatogenesis, suggesting an association between the abnormal programming of these regions and failure of germ cells progressing beyond meiosis.
精子发生和功能需要在生殖细胞中正确建立 DNA 甲基化模式。在这里，我们研究了人类精子发生过程中的全基因组 DNA 甲基化变化及其在精子发生障碍中的改变。我们发现精子发生与甲基组的重塑有关，包括初级精母细胞中 DNA 甲基化的整体下降，随后是选择性再甲基化，导致精子/精子特异性甲基组。精子/精子中的低甲基化区域富含 DMRT 和 SOX 家族成员和精子特异性基因的特定转录因子结合位点。有趣的是，虽然 SINE 在整个精子发生过程中表现出不同的甲基化，但 LINE 似乎免受 DNA 甲基化变化的影响。在精子发生障碍中，生殖细胞表现出相当大的 DNA 甲基化变化，这些变化在转座元件和参与精子发生的基因中显著富集。我们在精子发生障碍中检测到 SVA 和 L1HS 的低甲基化，表明这些区域的异常编程与生殖细胞减数分裂后无法进一步发育之间存在关联。
