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.

Graphical Abstract

中文翻译：

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Trps1 在小鼠 Leydig 细胞中充当 Sf-1 转录和睾酮合成的调节因子

不育症已引起全球关注，睾酮激素紊乱是男性不育症的常见原因。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。毛鼻指综合征1（Trps1）基因的研究最近集中在癌症方面；目前尚不清楚Trps1是否对男性生殖系统产生显着影响。在当前的研究中，利用单细胞RNA测序分析小鼠睾丸中毛鼻指综合征-1基因（Trps1 ）的表达和靶标下的裂解以及标签化和RNA测序来研究Trps1在小鼠Leydig细胞中的功能。使用腺相关病毒递送和条件敲除模型，Trps1的敲低增加了体外和体内睾酮合成。结果表明Trps1在Leydig细胞中大量表达。体内和体外Trps1缺乏后，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分泌均增加。此外， Trps1的破坏降低了组蛋白脱乙酰酶 1/2 的活性，并增加了Sf-1启动子中组蛋白 H3 的乙酰化，从而促进睾酮分泌。有趣的是，Sf-1 还通过激活转录因子 2 来调节Trps1的转录。这些结果表明，Trps1 靶向Sf-1，通过组蛋白乙酰化影响类固醇生成，并揭示了Trps1在小鼠 Leydig 细胞中发挥的关键作用。

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