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Int J Biol Sci 2022; 18(7):2807-2820. doi:10.7150/ijbs.70441 This issue Cite

Research Paper

BMI1 promotes spermatogonial stem cell maintenance by epigenetically repressing Wnt10b/β-catenin signaling

Jun Yu^1*, Cong Shen^2*, Meng Lin^3*, Xia Chen^4*, Xiuliang Dai⁵, Zhiran Li¹, Yunhao Wu¹, Yangbo Fu¹, Jinxing Lv⁶, Xiaoyan Huang^3✉, Bo Zheng^2,7✉, Fei Sun^1✉

1. Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China.
2. 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.
3. State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
4. Department of Obstetrics and Gynecology, Affiliated Hospital 2 of Nantong University and First People's Hospital of Nantong City, Nantong 226001, China.
5. Center of Clinical Reproductive Medicine, The Affiliated Changzhou Maternity and Child Health Care Hospital of Nanjing Medical University, Changzhou 213000, China.
6. Suzhou Dushu Lake Hospital (Dushu Lake Hospital Affiliated to Soochow University), Suzhou 215124, China.
7. NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Bo Zheng, 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. E-mail: bozhengedu.cn; Fei Sun, Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China. E-mail: sunfeiedu.cn; Xiaoyan Huang, State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China. E-mail: bbhxyedu.cn. More

Abstract

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 Wnt10b 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 in vivo. 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.

Keywords: Spermatogonial stem cells, Self-renewal, BMI1, Wnt10b, Wnt/β-catenin signaling

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