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

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.

BMI1 fine-tunes gene repression and activation to safeguard undifferentiated spermatogonia fate

“…These findings suggest BMI1 contributes to the activation of PI3K-Akt pathway by facilitating the deposition of repressive histone modifications on its negative regulators. A recent study reported that BMI1 represses Wnt10b/β-catenin signaling for undifferentiated spermatogonia maintenance ( Yu et al, 2022 ). In our study, we found that BMI1 binds Wnt10b modified with H2AK119ub1 and H3K27me3.…”

“…BMI1 is mainly expressed in undifferentiated spermatogonia, regulates proliferation of undifferentiated spermatogonia and maintains male fertility ( Komai et al, 2014 ; Dai et al, 2018 ). Recently, BMI1 has been reported to epigenetically repress Wnt10b/β-catenin signaling to promote spermatogonia stem cell maintenance ( Yu et al, 2022 ). BMI1 can assemble cPRC1 and ncPRC1 with distinct biochemical functions in cellular context-dependent manner ( Aranda et al, 2015 ).…”

Slc26a1 is not essential for spermatogenesis and male fertility in mice

“…After transfection with siRNA, GC-1 and GC-2 cells were seeded in 96-well plates at a density of 4 × 10 3 cells/well. Cell viability was evaluated using a cell counting kit-8 (CCK-8; Beyotime Institute of Biotechnology, Nantong, China), as previously described ( Chen et al, 2022a ; Xue et al, 2022 ; Yu et al, 2022 ). In the colony formation assay, 1,000 transfected cells were placed in 6-well plates; 2 mL DMEM containing 10% FBS was added to each well and changed after 6 d. After 2 weeks, the cells were fixed with methanol and stained with 0.1% crystal violet (Beyotime, Jiangsu, China) for 30 min, and the visible proliferating clumps were counted under a microscope (Carl Zeiss, Oberkochen, Germany).…”

BMI‐1 promotes breast cancer proliferation and metastasis through different mechanisms in different subtypes

“…As previously described, 18 , 19 , 20 , 21 the paraffin‐embedded tissues were dewaxed and hydrated, then antigen retrieval was performed by boiling samples in 10 mM sodium citrate buffer (pH 6.0). The sections were blocked with 1% BSA in PBS for 2 h and then incubated with primary antibody and secondary antibody successively.…”