BMI1 Drives Steroidogenesis Through Epigenetically Repressing the p38 MAPK Pathway

Abstract

Testosterone biosynthesis progressively decreases in aging males as a result of functional changes to the Leydig cells. Despite this, the underlying mechanism of steroidogenic process remains largely unclear. Using a gene knock-out approach, we and others have recently identified Bmi1 as an anti-aging gene. Herein, we investigate the role of BMI1 in steroidogenesis using mouse MLTC-1 and primary Leydig cells. We show that BMI1 can positively regulate testosterone production. Mechanistically, in addition to its known role in antioxidant activity, we also report that the p38 mitogen-activated protein kinase (MAPK) signaling is activated in BMI1-deficient cells, and ablation of the p38 MAPK pathway restores testosterone production. Furthermore, we reveal that BMI1 directly binds to the promoter region of p38 upstream kinases, Map3k3, thus modulating its chromatin status and expression. Consequently, this leads to repression of the p38 MAPK pathway thereby promoting steroidogenesis. Evidently, our findings uncover a novel epigenetic mechanism of BMI1 mediated gene silencing during steroidogenesis.