Kruse Alexander, Schneider Simon, Merges Gina Esther, Fröbius Andreas Christian, Forné Ignasi, Imhof Axel, Schorle Hubert, Steger Klaus
Department of Urology, Paediatric Urology and Andrology, Section Molecular Andrology, Biomedical Research Centre of the Justus-Liebig University Giessen, Giessen, Germany.
Department of Developmental Pathology, Institute of Pathology, University Hospital Bonn, Bonn, Germany.
Mol Hum Reprod. 2025 Jan 17;31(1). doi: 10.1093/molehr/gaaf003.
Protamine 2 (Prm2/PRM2), together with Protamine 1 (Prm1/PRM1), constitute the two protamines found in both murine and human sperm. During spermiogenesis in haploid male germ cells, chromatin undergoes significant condensation, a phase in which most histones are replaced by a species-specific ratio of these two protamines. Altered PRM1/PRM2 ratios are associated with subfertility and infertility in both male mice and men. Notably, during histone-to-protamine exchange, a small fraction of histones remains (ranging from 1% to 15%) bound to DNA. The regulatory roles of these residual histones, governed by post-translational modifications (PTMs), play a pivotal role in spermatogenesis, particularly in chromatin remodelling and epigenetic regulation of genes during sperm differentiation or even in early embryogenesis. In this study, utilizing a Prm2-deficient mouse model and conducting an analysis of sperm samples from men exhibiting either normozoospermia or atypical spermiograms, we observed alterations in the methylation and acetylation profiles of histones H3 and H4. Subsequent in-depth analysis revealed that discrepancies in protamine ratios do not significantly influence the PTMs of histones in testicular sperm. In murine epididymal sperm, altered protamine ratios are associated with reduced acetylation of histone H4 (H4ac), a phenomenon similarly observed in ejaculated sperm from men. In particular, H4K5ac and H4K12ac were identified as the two modifications that appear to decrease as a result of reduced Prm2/PRM2 levels. Our findings reveal that Protamine 2 is necessary for the maintenance of specific histone PTMs, such as acetylation, which is essential for proper spermatogenesis and particularly for chromatin remodelling.
鱼精蛋白2（Prm2/PRM2）与鱼精蛋白1（Prm1/PRM1）共同构成了在小鼠和人类精子中均能发现的两种鱼精蛋白。在单倍体雄性生殖细胞的精子发生过程中，染色质会经历显著的浓缩，在此阶段，大多数组蛋白会被这两种鱼精蛋白以物种特异性比例所取代。PRM1/PRM2比例的改变与雄性小鼠和男性的生育力低下及不育有关。值得注意的是，在组蛋白向鱼精蛋白的交换过程中，一小部分组蛋白（范围从1%到15%）仍与DNA结合。这些残留组蛋白的调控作用受翻译后修饰（PTMs）的支配，在精子发生中起着关键作用，尤其是在精子分化甚至早期胚胎发育过程中的染色质重塑和基因的表观遗传调控方面。在本研究中，利用Prm2缺陷小鼠模型并对表现为正常精子症或非典型精子图谱的男性的精子样本进行分析，我们观察到组蛋白H3和H4的甲基化和乙酰化谱发生了改变。随后的深入分析表明，鱼精蛋白比例的差异对睾丸精子中组蛋白的PTMs没有显著影响。在小鼠附睾精子中，鱼精蛋白比例的改变与组蛋白H4（H4ac）乙酰化的减少有关，这一现象在男性射出的精子中也同样观察到。特别是，H4K5ac和H4K12ac被确定为两种似乎因Prm2/PRM2水平降低而减少的修饰。我们的研究结果表明，鱼精蛋白2对于维持特定的组蛋白PTMs（如乙酰化）是必要的，而乙酰化对于正常的精子发生尤其是染色质重塑至关重要。
