BMI1 governs the maintenance of mouse GC-2 cells through epigenetic repression of Foxl1 transcription

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 (FoxI1) 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 beta-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.