Fam170a deficiency causes male infertility by impairing histone-to-protamine exchange during mouse spermiogenesis

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.