Androgens Regulate Ovarian Gene Expression Through Modulation of Ezh2 Expression and Activity

Area of Science:

• Reproductive Biology
• Molecular Endocrinology
• Epigenetics

Background:

• Androgen signaling is vital for ovarian physiology, including follicle development and ovulation.
• Androgen actions in granulosa cells involve both extranuclear and nuclear androgen receptor signaling.

Purpose of the Study:

• To elucidate the molecular mechanisms by which androgens regulate key genes involved in ovulation.
• To investigate the role of Ezh2 and microRNA-101 in androgen-mediated ovarian function.

Main Methods:

• Investigated androgen effects on PI3K/Akt pathway, Ezh2 phosphorylation, and miR-101 expression in mouse granulosa cells.
• Assessed the impact of Ezh2 inhibition on H3K27me3 marks and Runx1 gene expression.
• Utilized in vivo models to block androgen-induced Ezh2 inhibition and evaluate effects on ovulation.

Main Results:

• Androgens rapidly phosphorylate and inhibit Ezh2 via the PI3K/Akt pathway.
• Androgens induce miR-101 expression, leading to reduced Ezh2 protein levels over 24-48 hours.
• This process decreases H3K27me3 marks at the Runx1 promoter, increasing Runx1 mRNA and promoting LH-induced ovulation.
• Estrogen activates PI3K/Akt but does not induce miR-101 or long-term Ezh2 suppression, highlighting androgen specificity.

Conclusions:

• Androgen signaling orchestrates a long-term suppression of Ezh2 through miR-101 induction, which is essential for regulating Runx1 expression and ovulation.
• The findings reveal a novel extranuclear to intranuclear signaling cascade in androgen action within the ovary.
• This pathway is specific to androgens and plays a critical role in the physiological regulation of ovulation.