Robinson Research Institute, School of Biomedicine, Faculty of Health & Medical Sciences, University of Adelaide, Australia.
Indigenous Genomics, Telethon Kids Institute, Adelaide, Australia.
Nucleic Acids Res. 2023 Jul 7;51(12):5981-5996. doi: 10.1093/nar/gkad271.
Progesterone receptor (PGR) plays diverse roles in reproductive tissues and thus coordinates mammalian fertility. In the ovary, rapid acute induction of PGR is the key determinant of ovulation through transcriptional control of a unique set of genes that culminates in follicle rupture. However, the molecular mechanisms for this specialized PGR function in ovulation is poorly understood. We have assembled a detailed genomic profile of PGR action through combined ATAC-seq, RNA-seq and ChIP-seq analysis in wildtype and isoform-specific PGR null mice. We demonstrate that stimulating ovulation rapidly reprograms chromatin accessibility in two-thirds of sites, correlating with altered gene expression. An ovary-specific PGR action involving interaction with RUNX transcription factors was observed with 70% of PGR-bound regions also bound by RUNX1. These transcriptional complexes direct PGR binding to proximal promoter regions. Additionally, direct PGR binding to the canonical NR3C motif enable chromatin accessibility. Together these PGR actions mediate induction of essential ovulatory genes. Our findings highlight a novel PGR transcriptional mechanism specific to ovulation, providing new targets for infertility treatments or new contraceptives that block ovulation.
孕激素受体（PGR）在生殖组织中发挥多种作用，从而协调哺乳动物的生育能力。在卵巢中，PGR 的快速急性诱导是通过对一组独特基因的转录控制来决定排卵的关键决定因素，最终导致卵泡破裂。然而，排卵中这种特殊的 PGR 功能的分子机制还知之甚少。我们通过在野生型和同工型特异性 PGR 缺失小鼠中进行联合 ATAC-seq、RNA-seq 和 ChIP-seq 分析，组装了 PGR 作用的详细基因组图谱。我们证明，刺激排卵会迅速重新编程三分之二的染色质可及性，与基因表达的改变相关。观察到一种涉及与 RUNX 转录因子相互作用的卵巢特异性 PGR 作用，其中 70%的 PGR 结合区域也与 RUNX1 结合。这些转录复合物将 PGR 结合引导至近端启动子区域。此外，PGR 对经典 NR3C 基序的直接结合可实现染色质可及性。这些 PGR 作用共同介导必需的排卵基因的诱导。我们的发现强调了排卵特有的新型 PGR 转录机制，为不孕治疗或阻断排卵的新型避孕药具提供了新的靶点。
