Human-specific gene CT47 blocks PRMT5 degradation to lead to meiosis arrest

Chao Li; Yuming Feng; Zhenxin Fu; Junjie Deng; Yue Gu; Hanben Wang; Xin Wu; Zhengyun Huang; Yichen Zhu; Zhiwei Liu; Moli Huang; Tao Wang; Shijun Hu; Bing Yao; Yizhun Zeng; Chengji J Zhou; Steve D M Brown; Yi Liu; Antonio Vidal-Puig; Yingying Dong; Ying Xu

doi:10.1038/s41420-022-01139-6

Human-specific gene CT47 blocks PRMT5 degradation to lead to meiosis arrest

Cell Death Discov. 2022 Aug 2;8(1):345. doi: 10.1038/s41420-022-01139-6.

Authors

Chao Li¹, Yuming Feng², Zhenxin Fu¹, Junjie Deng¹, Yue Gu¹, Hanben Wang³, Xin Wu³, Zhengyun Huang¹, Yichen Zhu¹, Zhiwei Liu¹, Moli Huang¹, Tao Wang¹, Shijun Hu⁴, Bing Yao², Yizhun Zeng¹, Chengji J Zhou⁵, Steve D M Brown⁶, Yi Liu⁷, Antonio Vidal-Puig⁸, Yingying Dong⁹, Ying Xu¹⁰

Affiliations

¹ Cambridge-Su Genomic Resource Center, Jiangsu Key Laboratory of Neuropsychiatric Diseases, Medical School of Soochow University, Suzhou, Jiangsu, 215123, China.
² Department of Reproductive Medical Center, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China.
³ State Key Laboratory of Reproductive Medicine (SKLRM), Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
⁴ Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000, China.
⁵ Department of Biochemistry and Molecular Medicine, University of California at Davis, School of Medicine, Sacramento, CA, USA.
⁶ Medical Research Council (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, UK.
⁷ Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
⁸ University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, MDU MRC, Cambridge, UK.
⁹ Cambridge-Su Genomic Resource Center, Jiangsu Key Laboratory of Neuropsychiatric Diseases, Medical School of Soochow University, Suzhou, Jiangsu, 215123, China. yydong@suda.edu.cn.
¹⁰ Cambridge-Su Genomic Resource Center, Jiangsu Key Laboratory of Neuropsychiatric Diseases, Medical School of Soochow University, Suzhou, Jiangsu, 215123, China. yingxu@suda.edu.cn.

Abstract

Exploring the functions of human-specific genes (HSGs) is challenging due to the lack of a tractable genetic model system. Testosterone is essential for maintaining human spermatogenesis and fertility, but the underlying mechanism is unclear. Here, we identified Cancer/Testis Antigen gene family 47 (CT47) as an essential regulator of human-specific spermatogenesis by stabilizing arginine methyltransferase 5 (PRMT5). A humanized mouse model revealed that CT47 functions to arrest spermatogenesis by interacting with and regulating CT47/PRMT5 accumulation in the nucleus during the leptotene/zygotene-to-pachytene transition of meiosis. We demonstrate that testosterone induces nuclear depletion of CT47/PRMT5 and rescues leptotene-arrested spermatocyte progression in humanized testes. Loss of CT47 in human embryonic stem cells (hESCs) by CRISPR/Cas9 led to an increase in haploid cells but blocked the testosterone-induced increase in haploid cells when hESCs were differentiated into haploid spermatogenic cells. Moreover, CT47 levels were decreased in nonobstructive azoospermia. Together, these results established CT47 as a crucial regulator of human spermatogenesis by preventing meiosis initiation before the testosterone surge.

Abstract

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