Abstract
Progesterone receptor (PGR) co-ordinately regulates ovulation, fertilisation and embryo implantation through tissue-specific actions, but the mechanisms for divergent PGR action are poorly understood. Here we characterised PGR activity in mouse granulosa cells using combined ChIP-seq for PGR and H3K27ac and gene expression microarray. Comparison of granulosa, uterus and oviduct PGR-dependent genes showed almost complete tissue specificity in PGR target gene profiles. In granulosa cells 82% of identified PGR-regulated genes bound PGR within 3 kb of the gene and PGR binding sites were highly enriched in proximal promoter regions in close proximity to H3K27ac-modified active chromatin. Motif analysis showed highly enriched PGR binding to the PGR response element (GnACAnnnTGTnC), but PGR also interacted significantly with other transcription factor binding motifs. In uterus PGR showed far more tendency to bind intergenic chromatin regions and low evidence of interaction with other transcription factors. This is the first genome-wide description of PGR action in granulosa cells and systematic comparison of diverse PGR action in different reproductive tissues. It clarifies finely-tuned contextual PGR-chromatin interactions with implications for more targeted reproductive medicine.
Highlights
Progesterone (P4) is an essential reproductive hormone produced by the ovarian follicular granulosa cells immediately prior to ovulation
As Progesterone receptor (PGR) protein level was highest at 6 h post-human chorionic gonadotropin (hCG), we chose this time point to collect our samples for subsequent experiments
It is known that PGR plays diverse roles in reproductive tissues, enabling P4-PGR signalling to coordinate various physiological processes in female reproduction
Summary
Progesterone (P4) is an essential reproductive hormone produced by the ovarian follicular granulosa cells immediately prior to ovulation. PGR belongs to the 3-Ketosteroid receptor family (NR3C) and there are two isoforms of PGR, PGR-A and PGR-B, which are identical apart from an additional N-terminal domain in PGR-B10 Both isoforms are present in most PGR-positive cells; PGR-A is more important for ovarian and uterine functions whereas PGR-B plays the main role in the murine mammary gland[11,12]. PGR plays a number of roles in the reproductive tract, such as regulating inflammation in the ovaries, ciliated transporting of embryos and promoting decidualisation and implantation in the uterus[13,20,21]. These are Female Reproduction Group, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, 27709, USA. An understanding of the mechanism responsible for the diversity in PGR action between different target tissues may reveal key details of PGR functions; considering how differently PGR behaves between cell types, including normal versus cancerous cells, it is valuable to actively investigate these contrasting regulatory mechanisms
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