Bo Zheng1, Juanjuan Liu2, Xiaodan Shi3, Jinfu Xu4, Ke Zhang5, Hui Zhou6, Tiantian Wu4, Xiaoyan Huang4, Cong Shen1, Yuting Liang7, Dan Zhao8, Yueshuai Guo4. 1. 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, Jiangsu, China. 2. Reproductive Medicine Center, The Second Affiliated Hospital of Soochow University Suzhou 215004, Jiangsu, China. 3. Department of Reproduction, The Affiliated Obstetrics and Gynecology Hospital with Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital Nanjing 210004, Jiangsu, China. 4. State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University Nanjing 211166, Jiangsu, China. 5. Department of Urology, The Second Affiliated Hospital of Soochow University Suzhou 215004, Jiangsu, China. 6. Human Reproductive and Genetic Center, Affiliated Hospital of Jiangnan University Wuxi 214122, Jiangsu, China. 7. Center for Clinical Laboratory, The First Affiliated Hospital of Soochow University Suzhou 215006, Jiangsu, China. 8. Fourth Affiliated Hospital of Jiangsu University Zhenjiang 212008, Jiangsu, China.
Abstract
OBJECTIVES: Studies have demonstrated that B lymphoma Mo-MLV insertion region 1 (BMI1) plays an important role in male reproductive function and the regulation of spermatogonia proliferation. However, whether BMI1 exerts a similarly important function in spermatocyte development remains unclear. METHODS: In this study, we investigated the role of BMI1 in spermatocyte development using a mouse spermatocyte-derived cell line (GC-2) and a Bmi1-knockout (KO) mouse model. RESULTS: We demonstrated that BMI1 promoted the proliferation and inhibited the apoptosis of GC-2 cells. Mechanistically, we presented in vitro and in vivo evidence showing that BMI1 binds to the promoter region of the forkhead box L1 (Foxl1) gene, sequentially driving chromatin remodeling and gene silencing. BMI1, which functions as a classical polycomb protein, was found to direct the transcriptional repression of Foxl1 through increasing the H2AK119ub level and reducing that of H3K4me3 in the promoter region of Foxl1. Our results further indicated that the knockdown of Foxl1 expression significantly enhanced cell proliferation via activating β-catenin signaling in BMI1-deficient GC-2 cells. CONCLUSIONS: Collectively, our study revealed for the first time the existence of an epigenetic mechanism involving BMI1-mediated gene silencing in GC-2 cells development and provided potential targets for the treatment of male infertility. AJTR
OBJECTIVES: Studies have demonstrated that B lymphoma Mo-MLV insertion region 1 (BMI1) plays an important role in male reproductive function and the regulation of spermatogonia proliferation. However, whether BMI1 exerts a similarly important function in spermatocyte development remains unclear. METHODS: In this study, we investigated the role of BMI1 in spermatocyte development using a mouse spermatocyte-derived cell line (GC-2) and a Bmi1-knockout (KO) mouse model. RESULTS: We demonstrated that BMI1 promoted the proliferation and inhibited the apoptosis of GC-2 cells. Mechanistically, we presented in vitro and in vivo evidence showing that BMI1 binds to the promoter region of the forkhead box L1 (Foxl1) gene, sequentially driving chromatin remodeling and gene silencing. BMI1, which functions as a classical polycomb protein, was found to direct the transcriptional repression of Foxl1 through increasing the H2AK119ub level and reducing that of H3K4me3 in the promoter region of Foxl1. Our results further indicated that the knockdown of Foxl1 expression significantly enhanced cell proliferation via activating β-catenin signaling in BMI1-deficient GC-2 cells. CONCLUSIONS: Collectively, our study revealed for the first time the existence of an epigenetic mechanism involving BMI1-mediated gene silencing in GC-2 cells development and provided potential targets for the treatment of male infertility. AJTR
Authors: Mariana de Napoles; Jacqueline E Mermoud; Rika Wakao; Y Amy Tang; Mitusuhiro Endoh; Ruth Appanah; Tatyana B Nesterova; Jose Silva; Arie P Otte; Miguel Vidal; Haruhiko Koseki; Neil Brockdorff Journal: Dev Cell Date: 2004-11 Impact factor: 12.270
Authors: Kenneth I Aston; Philip J Uren; Timothy G Jenkins; Alan Horsager; Bradley R Cairns; Andrew D Smith; Douglas T Carrell Journal: Fertil Steril Date: 2015-09-08 Impact factor: 7.329