Cheng Jinmei, Gu Yimin, Wang Yueming, Xun Junjie, Wang Guishuan, Wang Yu, Wang Jianyu, Li Yinchuan, Sun Fei
Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China.
Department of Obstetrics and Gynecology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, China.
Nucleic Acids Res. 2025 Jan 24;53(3). doi: 10.1093/nar/gkaf023.
Chromatin remodeling, which involves the histone-to-protamine exchange process during spermiogenesis, is crucial for sperm nuclear condensation and male fertility. However, the key regulators and underlying molecular mechanisms involved in this process remain largely unexplored. In this study, we discovered that deficiency in the family with sequence similarity 170 member A (Fam170a) led to abnormal sperm nuclear morphology and male infertility in mice, mirroring the observation of very low Fam170a transcription levels in sperm of infertile men with teratozoospermia. Further investigation revealed that Fam170a plays a significant role in the histone-to-protamine chromatin remodeling process. This was evidenced by the earlier core histone removal, accelerated translation and degradation of transition proteins, and reduced protamine incorporation during spermiogenesis in Fam170a-deleted mice. Mechanistically, we found that Fam170a interacts with chromatin remodeling-associated proteins and regulates the transcription of genes related to chromatin remodeling. Notably, Fam170a directly interacts with the deubiquitinating enzyme Usp7 and facilitates its nuclear translocation in elongating sperm, enhancing the deubiquitinating activity of Usp7 on testis-specific histone H2A and H2B variants. Collectively, our findings identify Fam170a as a previously unrecognized key regulator of sperm chromatin remodeling and suggest that histone deubiquitination may play an essential role in the histone-to-protamine exchange process.
染色质重塑涉及精子发生过程中的组蛋白与鱼精蛋白交换过程，对精子核凝聚和男性生育能力至关重要。然而，这一过程中涉及的关键调节因子和潜在分子机制在很大程度上仍未被探索。在本研究中，我们发现序列相似性家族170成员A（Fam170a）的缺失导致小鼠精子核形态异常和雄性不育，这与畸精子症不育男性精子中Fam170a转录水平极低的观察结果一致。进一步研究表明，Fam170a在组蛋白向鱼精蛋白的染色质重塑过程中起重要作用。这在Fam170a缺失小鼠的精子发生过程中得到了证实，表现为核心组蛋白去除更早、过渡蛋白的翻译和降解加速以及鱼精蛋白掺入减少。从机制上讲，我们发现Fam170a与染色质重塑相关蛋白相互作用，并调节与染色质重塑相关基因的转录。值得注意的是，Fam170a直接与去泛素化酶Usp7相互作用，并促进其在伸长精子中的核转位，增强Usp7对睾丸特异性组蛋白H2A和H2B变体的去泛素化活性。总的来说，我们的研究结果确定Fam170a是一种先前未被认识的精子染色质重塑关键调节因子，并表明组蛋白去泛素化可能在组蛋白向鱼精蛋白的交换过程中起重要作用。
