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Progesterone receptor (PGR)-mediated transcriptional networks in human ovulatory follicles: Identification of SOX9 as a novel PGR-downstream mediator [ChIP-seq]

ABSTRACT: Progesterone receptor (PGR) is an essential transcription factor for successful ovulation. Clinically, PGR inhibitors have been used as emergency contraceptives due to their ability to delay or block ovulation. While much of the current understanding of PGR’s function has been derived from animal models, the specific downstream target genes and pathways PGR regulates in human ovulatory follicles remain largely unexplored. In the present study, we utilized a human granulosa cell (hGLC) model that mimics preovulatory hCG-induced increases in PGR expression and progesterone production, combined with a PGR inhibitor (RU486), to identify hCG-induced, PGR-regulated genes in human ovulatory follicles. RNA-Seq and ChIP-Seq analyses revealed numerous genes regulated by PGR in response to human chorionic gonadotropin (hCG) treatment for 12 h, which are involved in diverse biological processes, including metabolism, steroidogenesis, signaling activation, cell cycle regulation, and transcriptional control. By comparing these findings with the existing data from PgrKO mouse models, we also identified both conserved and species-specific PGR-regulated genes. Notably, SOX9 was identified as a human-specific, hCG-induced PGR-target gene in hGLCs. A further characterization study using dominant follicle samples collected before and at different times after ovulatory hCG administration from regularly cycling women demonstrated that SOX9 expression is predominantly induced in the granulosa cells of ovulatory follicles and persists in the developing corpus luteum. Functional studies showed that SOX9 knockdown by siRNA reduced progesterone production and the expression of steroidogenesis-related genes (CYP11A1 and STAR) in hGLCs. In summary, the present finding provides the first comprehensive list of preovulatory PGR-downstream genes in human granulosa cells and unveils SOX9 as a novel human-specific ovulatory transcription factor with potential roles in steroidogenesis. This foundational information not only enhances our understanding of the PGR-regulated ovulatory pathway but also provides a critical resource for developing improved strategies to manage women’s fertility.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286910 | GEO | 2026/04/17

REPOSITORIES: GEO

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Project description:Progesterone receptor (PGR) is an essential transcription factor for successful ovulation. Clinically, PGR inhibitors have been used as emergency contraceptives due to their ability to delay or block ovulation. While much of the current understanding of PGR’s function has been derived from animal models, the specific downstream target genes and pathways PGR regulates in human ovulatory follicles remain largely unexplored. In the present study, we utilized a human granulosa cell (hGLC) model that mimics preovulatory hCG-induced increases in PGR expression and progesterone production, combined with a PGR inhibitor (RU486), to identify hCG-induced, PGR-regulated genes in human ovulatory follicles. RNA-Seq and ChIP-Seq analyses revealed numerous genes regulated by PGR in response to human chorionic gonadotropin (hCG) treatment for 12 h, which are involved in diverse biological processes, including metabolism, steroidogenesis, signaling activation, cell cycle regulation, and transcriptional control. By comparing these findings with the existing data from PgrKO mouse models, we also identified both conserved and species-specific PGR-regulated genes. Notably, SOX9 was identified as a human-specific, hCG-induced PGR-target gene in hGLCs. A further characterization study using dominant follicle samples collected before and at different times after ovulatory hCG administration from regularly cycling women demonstrated that SOX9 expression is predominantly induced in the granulosa cells of ovulatory follicles and persists in the developing corpus luteum. Functional studies showed that SOX9 knockdown by siRNA reduced progesterone production and the expression of steroidogenesis-related genes (CYP11A1 and STAR) in hGLCs. In summary, the present finding provides the first comprehensive list of preovulatory PGR-downstream genes in human granulosa cells and unveils SOX9 as a novel human-specific ovulatory transcription factor with potential roles in steroidogenesis. This foundational information not only enhances our understanding of the PGR-regulated ovulatory pathway but also provides a critical resource for developing improved strategies to manage women’s fertility.

Project description:Determining the spatial and temporal expression of genes involved in the ovulatory pathway is critical for the understanding of the role of each estrogen receptor in the modulation of folliculogenesis and ovulation. Estrogen receptor (ER) b is highly expressed in ovarian granulosa cells and mice lacking ERb (bERKO) are subfertile due to inefficient ovulation. Previous work has focused on isolated granulosa cells or cultured follicles and while informative, provides confounding results due to the heterogeneous cell types present including granulosa, theca and oocytes and exposure to in vitro conditions. Herein, we isolated preovulatory granulosa cells from WT and ERb-null mice using laser capture microdissection to examine the genomic transcriptional response downstream of PMSG (mimicking FSH) and PMSG/hCG (mimicking LH) stimulation. This allows for a direct comparison of in vivo granulosa cells at the same stage of development from both WT and ERb-null ovaries. ERb-null granulosa cells showed altered expression of genes known to be regulated by FSH (Akap12 and Runx2) as well as not previously reported (Arnt2 and Pou5f1) in WT granulosa cells. Our analysis also identified 304 genes not previously associated with ERb in granulosa cells. LH responsive genes including Abcb1b and Fam110c show reduced expression in ERb-null granulosa cells; however novel genes including Rassf2 and Megf10 were also identified as being downstream of LH signaling in granulosa cells. Collectively, our data suggests that granulosa cells from ERb-null ovaries may not be appropriately differentiated and are unable to respond properly to gonadotropin stimulation We used microarray to compare the gene expression profiles of wiltype (WT) and Erb-null (bERKO) preovulatory granulosa cells as they respond to either PMSG or PMSG+hCG treatments. Laser microdissection was used to collect a purified population of granulosa cells only from preovulatory follicles. We chose to compre the response to PMSG or PMSG+hCG of granulosa cells collected from either WT and bERKO preovulatory follicles. We chose to collect cells 48h after mice were treated with PMSG to compare the gene expression profile ot preovulatory granulosa cells. We also studied the response of these cells to LH (or hCG) as we collected cells 4h after mice were treated with hCG (peak of transcriptional response to hCG).

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Progesterone receptor (PGR)-mediated transcriptional networks in human ovulatory follicles: Identification of SOX9 as a novel PGR-downstream mediator [ChIP-seq]

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