Key Laboratory of Stem Cell Engineering and Regenerative Medicine of Fujian Province University, Fujian Medical University, Fuzhou, 350122, People's Republic of China.
Department of Histology and Embryology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, People's Republic of China.
Cell Biol Toxicol. 2023 Dec;39(6):3141-3157. doi: 10.1007/s10565-023-09823-8. Epub 2023 Aug 2.
Infertility has attracted global concern, and disruption of testosterone is a common cause of male infertility. Exploring the critical factors in testosterone biosynthesis may provide new insights for disease research and clinical therapy. Research on trichorhinophalangeal syndrome-1 (Trps1) gene has recently been focus on cancers; it is yet unknown whether Trps1 produces a marked effect in the male reproductive system. In the current study, single-cell RNA sequencing analysis of trichorhinophalangeal syndrome-1 gene (Trps1) expression in mouse testes and cleavage under targets and tagmentation and RNA sequencing were utilized to investigate the functionality of Trps1 in mouse Leydig cells. Knockdown of Trps1 increased testosterone synthesis in vitro and vivo using adeno-associated viral delivery and conditional knockout models. The results showed that Trps1 was abundantly expressed in Leydig cells. The expression levels of both steroidogenic factor-1 (Sf-1) and steroidogenic enzymes (Cyp11a1, Hsd3b, Cyp17a1, and Hsd17b3) as well as testosterone secretion were increased after Trps1 deficiency in vivo and vitro. Furthermore, disruption of Trps1 reduced histone deacetylase 1/2 activity and increased histone H3 acetylation in the Sf-1 promoter, thereby promoting testosterone secretion. Interestingly, Sf-1 also regulated the transcription of Trps1 through activating transcription factor 2. These results indicate that Trps1 targets Sf-1 to affect steroidogenesis through histone acetylation and shed light on the critical role of Trps1 functioning in the mouse Leydig cells.
不育症引起了全球关注，而睾酮的紊乱是男性不育的常见原因。探索睾酮生物合成的关键因素可能为疾病研究和临床治疗提供新的见解。最近，人们对 trichorhinophalangeal 综合征-1（Trps1）基因的研究集中在癌症上；尚不清楚 Trps1 是否对男性生殖系统产生显著影响。在本研究中，利用单细胞 RNA 测序分析了小鼠睾丸中 trichorhinophalangeal 综合征-1（Trps1）基因的表达，并采用靶向切割和 RNA 测序技术研究了 Trps1 在小鼠 Leydig 细胞中的功能。腺相关病毒递送和条件性敲除模型的体外和体内研究表明，Trps1 的敲低增加了睾酮的合成。结果表明，Trps1 在 Leydig 细胞中大量表达。体内和体外 Trps1 缺失后，类固醇生成因子-1（Sf-1）和类固醇生成酶（Cyp11a1、Hsd3b、Cyp17a1 和 Hsd17b3）的表达水平以及睾酮的分泌均增加。此外，Trps1 的破坏降低了 Sf-1 启动子中的组蛋白去乙酰化酶 1/2 活性，并增加了组蛋白 H3 的乙酰化，从而促进了睾酮的分泌。有趣的是，Sf-1 还通过激活转录因子 2 调节 Trps1 的转录。这些结果表明，Trps1 通过组蛋白乙酰化靶向 Sf-1 影响类固醇生成，并揭示了 Trps1 在小鼠 Leydig 细胞中发挥作用的关键作用。
