PHF7 Modulates BRDT Stability and Histone-to-Protamine Exchange during Spermiogenesis

• Published in: Cell reports (Cambridge) 2020-07, Vol.32 (4), p.107950-107950, Article 107950
• Main Authors: Kim, Chang Rok, Noda, Taichi, Kim, Hyunkyung, Kim, Gibeom, Park, Seongwan, Na, Yongwoo, Oura, Seiya, Shimada, Keisuke, Bang, Injin, Ahn, Jun-Yeong, Kim, Yong Ryoul, Oh, Se Kyu, Choi, Hee-Jung, Kim, Jong-Seo, Jung, Inkyung, Lee, Ho, Okada, Yuki, Ikawa, Masahito, Baek, Sung Hee
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; BRDT; Cell Nucleus - metabolism; Chromatin - metabolism; Chromatin Assembly and Disassembly; Gene Knock-In Techniques - methods; H3K14ub; H4 hyperacetylation; HEK293 Cells; histone removal; histone-to-protamine exchange; Histones - metabolism; Humans; Male; Meiosis; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; PHF7; Protamines - metabolism; Spermatids - metabolism; Spermatogenesis - genetics; Spermatogenesis - physiology; Spermatozoa - metabolism; spermiogenesis; Testis - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107950

Spermatogenesis is a complex process of sperm generation, including mitosis, meiosis, and spermiogenesis. During spermiogenesis, histones in post-meiotic spermatids are removed from chromatin and replaced by protamines. Although histone-to-protamine exchange is important for sperm nuclear condensation, the underlying regulatory mechanism is still poorly understood. Here, we identify PHD finger protein 7 (PHF7) as an E3 ubiquitin ligase for histone H3K14 in post-meiotic spermatids. Generation of Phf7-deficient mice and Phf7 C160A knockin mice with impaired E3 ubiquitin ligase activity reveals defects in histone-to-protamine exchange caused by dysregulation of histone removal factor Bromodomain, testis-specific (BRDT) in early condensing spermatids. Surprisingly, E3 ubiquitin ligase activity of PHF7 on histone ubiquitination leads to stabilization of BRDT by attenuating ubiquitination of BRDT. Collectively, our findings identify PHF7 as a critical factor for sperm chromatin condensation and contribute to mechanistic understanding of fundamental phenomenon of histone-to-protamine exchange and potential for drug development for the male reproduction system. [Display omitted] •PHF7 is an E3 ubiquitin ligase that ubiquitinates histone H3 at lysine 14•PHF7 is critical for histone-to-protamine exchange during spermiogenesis•PHF7 controls BRDT stability during histone removal in early condensing spermatids•PHF7 attenuates the ubiquitination of BRDT via histone ubiquitination Histone-to-protamine exchange is essential for functional sperm. Kim et al. demonstrate that PHF7 is an E3 ubiquitin ligase for histone H3, and that PHF7-mediated histone ubiquitination regulates BRDT stability during histone removal. Mice with impaired Phf7 show dysfunctional sperm caused by defects in histone ubiquitination and histone-to-protamine exchange.