Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China.
State Key Laboratory of Reproductive Medicine, Center for Reproduction and Genetics, Suzhou Municipal Hospital, the Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou 215002, China.
Int J Biol Sci. 2022 Apr 4;18(7):2807-2820. doi: 10.7150/ijbs.70441. eCollection 2022.
The self-renewal of spermatogonial stem cells (SSCs) requires a special microenvironment and is strictly controlled. Previously, we identified BMI1 as a key regulator of spermatogenesis in a knock-out mouse model. However, the mechanisms by which BMI1 regulates SSC maintenance remain largely unknown. Herein, we show that BMI1 is essential for SSC maintenance. BMI1 directs the transcriptional repression of target genes by increasing H2AK119ub and reducing H3K4me3 in SSCs. Furthermore, BMI1 inhibition resulted in the transcriptional activation of and thereby promoted the nuclear translocation of β-catenin in SSCs. Importantly, the suppression of Wnt/β-catenin signaling restored both the cytoplasmic expression of β-catenin and SSC maintenance in BMI1-deficient SSCs. Finally, we demonstrated that Wnt/β-catenin signaling was also involved in BMI1-mediated SSC maintenance . Altogether, our study not only reveals a novel mechanism for BMI1 in the process of SSC maintenance, but also provides a potential new strategy for treating male infertility.
精原干细胞（SSCs）的自我更新需要特殊的微环境，并受到严格控制。此前，我们在敲除小鼠模型中发现 BMI1 是精子发生的关键调节因子。然而，BMI1 调节 SSC 维持的机制在很大程度上尚不清楚。本文中，我们证明了 BMI1 对于 SSC 的维持是必需的。BMI1 通过增加 SSCs 中的 H2AK119ub 和减少 H3K4me3 来指导靶基因的转录抑制。此外，BMI1 的抑制导致 的转录激活，从而促进 SSCs 中 β-连环蛋白的核易位。重要的是，抑制 Wnt/β-连环蛋白信号转导恢复了 BMI1 缺陷型 SSCs 中 β-连环蛋白的细胞质表达和 SSC 的维持。最后，我们证明了 Wnt/β-连环蛋白信号转导也参与了 BMI1 介导的 SSC 维持。总之，我们的研究不仅揭示了 BMI1 在 SSC 维持过程中的新机制，而且为治疗男性不育提供了一种潜在的新策略。
