DataSheet2_Polycomb subunit Pcgf2 mediates ovulation and fertility through transcriptional regulation progesterone receptor.pdf

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.

卵巢滤泡是支撑卵母细胞发育的基本结构，为后代提供成熟的卵母细胞。此过程需要颗粒细胞（GCs）对中期激素激增做出反应，通过一系列基因转录表达变化，导致GC增殖和分化。表观遗传介质，多梳抑制复合物1（PRC1）已被报道在胎儿卵巢发育中发挥作用。然而，其与滤泡发生和排卵的功能相关性尚不明确。在本研究中，我们证明了PRC1的关键组分PCGF2的选择性耗竭导致滤泡丢失、排卵缺陷以及发情周期延长，从而在雌性小鼠中导致亚不育。PCGF2的表达存在于生长滤泡的GCs中，并在人绒毛膜促性腺激素（hCG）刺激后增加。PCGF2与关键排卵基因孕酮受体（Pgr）的启动子结合，并在hCG激增后通过靶向H2AK119ub1的表观遗传修饰上调Pgr的表达。一致地，Pgr下游基因的表达也急剧下降，导致GC特异性Pcgf2敲除小鼠的滤泡破裂失败和卵母细胞被黄体捕获。总之，我们的研究确定了PCGF2通过调节激素受体表达对于滤泡发生和排卵的必要性。