Polycomb subunit Pcgf2 mediates ovulation and fertility through transcriptional regulation progesterone receptor

Abstract

Ovarian follicles are the fundamental structure to support oocyte development, which provides mature oocytes for offspring. This process requires granulosa cells (GCs) to respond to the midcycle surge of hormones, leading to GC proliferation and differentiation by a series of genes’ transcriptional expression changes. Epigenetic mediator, Polycomb Repressive Complex 1 (PRC1) has been reported to function in fetal ovarian development. However, its functional relevance to folliculogenesis and ovulation remains unknown. In this study, we demonstrated that GC-selective depletion of PCGF2, a key component of PRC1, led to the loss of follicles, ovulation defects, and a lengthened estrus cycle, resulting in subfertility in female mice. The expression of PCGF2 is in the GCs of growing follicles and increases after human chorionic gonadotropin (hCG) stimulation. PCGF2 bound to the promoter of the key ovulation gene progesterone receptor (Pgr) and upregulated the expression of Pgr by targeting the epigenetic modification of H2AK119ub1 after hCG surge. Consistently, the expression of downstream genes of Pgr also sharply decreased, which resulted in the follicular rupture failed and oocyte entrapped in corpus luteum in GC-specific Pcgf2 knockout mice. Together, our study identified that PCGF2 is essential for folliculogenesis and ovulation via modulating hormone receptor expression.

Polycomb repressive complex 1 modulates granulosa cell proliferation in early folliculogenesis to support female reproduction

“…Although WGS data identified the MEL18 mutant, there was little difference in ovarian fertility between the mcKO and WT groups in our mouse models. A recent study reported that the deletion of Mel18 terminated female fertility at 10 months with fewer pups 34 . However, this reproductive damage was still less significant than the clinical characteristics observed in the patient in the present study.…”

“…However, unlike the severe POI defects, the morphology and number of follicles had minimal difference between 8-month-old mcKO and WT ovaries. However, the mcKO group had a larger number of SFs than WT, probably reflecting impaired development of SFs induced by the ovulation defects [34] (Figure 1C, E). Meanwhile, BMI1, the MEL18 homolog [35,39,40], exhibited a similar expression pattern in ovaries (Figure 1D), indicating that simultaneous deletion of Bmi1/Mel18 in GCs may be necessary to eliminate their functional redundancy.…”

“…For instance, BMI1 regulates progesterone receptor ubiquitination in the uteruses, essential for embryo implantation in mice and humans 33 . Furthermore, GC-specific depletion of Mel18 , a homologue of Bmi1 , leads to an early onset of infertility by ovulation defects in 10-month-old mice 34 .…”