Zhang Ke, Xu Jinfu, Ding Yue, Shen Cong, Lin Meng, Dai Xiuliang, Zhou Hui, Huang Xiaoyan, Xue Boxin, Zheng Bo
Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
Biochem Biophys Res Commun. 2021 Nov 1;583:169-177. doi: 10.1016/j.bbrc.2021.10.074.
Spermatogonia are accountable for spermatogenesis and male fertility, but the underlying mechanisms involved in spermatogonia maintenance are not clear. B lymphoma Mo-MLV insertion region 1 (BMI1) is a key component of epigenetic silencers. BMI1 is essential for stem-cell maintenance. Here, we attempted to uncover the role of BMI1 in spermatogonia maintenance using a mouse spermatogonia cell line (GC-1) and Bmi1-knockout (KO) mouse model. We showed that BMI1 promoted the proliferation and inhibited apoptosis of GC-1 cells. Mechanistically, we present in vitro and in vivo evidence to show that BMI1 binds to the promoter region of the Protein tyrosine phosphatase receptor type M (PTPRM) gene, thereby driving chromatin remodeling and gene silencing. Knockdown of Ptprm expression significantly improved spermatogonia proliferation in BMI1-deficient GC-1 cells. Collectively, our data show, for the first time, an epigenetic mechanism involving in BMI1-mediated gene silencing in spermatogonia maintenance, and provide potential targets for the treatment of male infertility.
精原细胞负责精子发生和男性生育能力，但精原细胞维持所涉及的潜在机制尚不清楚。B淋巴瘤Mo-MLV插入区域1（BMI1）是表观遗传沉默因子的关键组成部分。BMI1对干细胞维持至关重要。在此，我们试图使用小鼠精原细胞系（GC-1）和Bmi1基因敲除（KO）小鼠模型来揭示BMI1在精原细胞维持中的作用。我们发现BMI1促进GC-1细胞的增殖并抑制其凋亡。从机制上讲，我们提供了体外和体内证据表明BMI1与蛋白酪氨酸磷酸酶受体M型（PTPRM）基因的启动子区域结合，从而驱动染色质重塑和基因沉默。敲低Ptprm表达可显著改善BMI1缺陷型GC-1细胞中的精原细胞增殖。总体而言，我们的数据首次展示了一种涉及BMI1介导的基因沉默在精原细胞维持中的表观遗传机制，并为男性不育症的治疗提供了潜在靶点。
