Loss of histone reader Phf7 leads to immune pathways activation via endogenous retroviruses during spermiogenesis
Jianxing Cheng,
Tongtong Li,
Zhongjie Zheng,
Xueguang Zhang,
Mengyang Cao,
Wenhao Tang,
Kai Hong,
Rui Zheng,
Jichun Shao,
Xiaomiao Zhao,
Hui Jiang,
Wenming Xu,
Haocheng Lin
Affiliations
Jianxing Cheng
Department of Urology, Peking University Third Hospital, Peking University, Beijing, China; Department of Reproductive Medicine Center, Peking University Third Hospital, Peking University, Beijing, China
Tongtong Li
Department of Obstetrics/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China
Zhongjie Zheng
Department of Urology, Peking University Third Hospital, Peking University, Beijing, China; Department of Reproductive Medicine Center, Peking University Third Hospital, Peking University, Beijing, China
Xueguang Zhang
Department of Obstetrics/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China
Mengyang Cao
Department of Urology, Peking University Third Hospital, Peking University, Beijing, China; Department of Reproductive Medicine Center, Peking University Third Hospital, Peking University, Beijing, China
Wenhao Tang
Department of Urology, Peking University Third Hospital, Peking University, Beijing, China; Department of Reproductive Medicine Center, Peking University Third Hospital, Peking University, Beijing, China; Department of Human Sperm Bank, Peking University Third Hospital, Peking University, Beijing, China
Kai Hong
Department of Urology, Peking University Third Hospital, Peking University, Beijing, China; Department of Reproductive Medicine Center, Peking University Third Hospital, Peking University, Beijing, China
Rui Zheng
Department of Obstetrics/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China
Jichun Shao
Department of Urology, Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Chengdu, Sichuan, China
Xiaomiao Zhao
Department of Reproductive Medicine, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Road, Guangzhou 510080, China
Hui Jiang
Department of Urology, Peking University Third Hospital, Peking University, Beijing, China; Department of Reproductive Medicine Center, Peking University Third Hospital, Peking University, Beijing, China; Corresponding author
Wenming Xu
Department of Obstetrics/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Corresponding author
Haocheng Lin
Department of Urology, Peking University Third Hospital, Peking University, Beijing, China; Department of Reproductive Medicine Center, Peking University Third Hospital, Peking University, Beijing, China; Corresponding author
Summary: Genetic studies have elucidated the critical roles of Phf7 in germline development in animals; however, the exact etiology of Phf7 mutations leading to male infertility and the possibility of mechanism-based therapy are still unclear and warrant further investigation. Using the Phf7 knockout mouse model, we verified that genetic defects were responsible for male infertility by preventing histone-to-protamine exchange, as previously reported. The deficiency of spermatogenesis caused by Phf7 deletion through the endogenous retrovirus-mediated activation of the immune pathway is a common mechanism of infertility. Furthermore, we identified PPARα as a promising target of immunity and inflammation in the testis, where endogenous retroviruses are suppressed, and Phf7 as a crucial regulator of endogenous retrovirus-mediated immune regulation and revealed its role as an epigenetic reader. The loss of Phf7 activates immune pathways, which can be rescued by the PPARα agonist astaxanthin. These results showed that astaxanthin is a potential therapeutic agent for treating male infertility. The findings in our study provide insights into the molecular mechanisms underlying male infertility and suggest potential targets for future research and therapeutic development.
