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Progesterone differentially affects the transcriptomic profiles of cow endometrial cell types

ABSTRACT: In this study, whole transcriptome changes induced by P4 were analysed by RNAseq following laser capture microdissection (LCM) of endometrial biopsies to isolate LE, GE and ST cells. The study was performed in cows without any sign of uterine disease (as assessed by uterine cytology). At 45 days postpartum, the presence of a Corpus Luteum (CL) assessed by ultrasonography and plasma P4 concentrations were used to categorise healthy cows at 45 days postpartum determine if cows were in luteal phase (CL, P4 concentrations ≥1 ng/ml; n=4) or not (no CL, P4 concentrations < 1ng/ml; n=9). Overall, endometrial LE, GE, and ST cells shown specific transcriptomic profiles with different proportions and type of genes expressed over 10 tpm. Most of the genes differentially expressed (DEGs) in response to P4 were cell type-specific (93.9%). Genes involved in cell cycle and nuclear division were under-expressed in presence of P4 in GE and LE, highlighting the anti-proliferative action of P4 in epithelial cells. Elevated P4 concentrations were also associated with the under-expression of estrogen receptor 1 (ESR1) in GE and of oxytocin receptor (OXTR) in GE and ST. In ST, transcription factors such as SOX17 and FOXA2 , as well as interferon related genes which are known to regulate uterine epithelial–stromal crosstalk conveying to endometrial receptivity for embryo implantation, were over-expressed under P4. The results from this study show that progesterone regulates endometrial function in a cell type specific way, which looks independent of the expression of its main receptor PGR. These novel insights into uterine physiology, stand the cell compartment, rather than the whole tissue, as a physiological unit.

ORGANISM(S): Bos taurus

PROVIDER: GSE182932 | GEO | 2021/12/03

REPOSITORIES: GEO

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Project description:Background: Physiological inflammation of the uterus postpartum is essential for the reparative processes of involution after calving. In the majority of cows, this inflammation is resolved and homeostasis is restored. However, in a significant subset, inflammation persists and contributes to tissue damage, pathology and subfertility. Transcriptomic differences of immune genes between cattle that resolve inflammation and those that develop uterine disease have been detected as early as 7 days postpartum (DPP) suggesting that the host immune response plays an important role in disease outcome. Results: Here, we extensively characterise the immune response at the transcriptomic level in endometrial epithelial cells from post-partum dairy cows phenotyped for both clinical and sub-clinical forms of uterine disease. We address the hypothesis that excessive expression of endometrial inflammatory molecules contributes to development of endometritis. Classification of cattle (n=112) as healthy or with uterine disease (purulent vaginal discharge; PVD and cytological endometritis; CYTO) was based on vaginal mucus score and >18% polymorphonuclear cell infiltrate into the endometrium at 21 DPP. RNA-seq analysis of endometrial epithelial cells collected using cytobrushes identified differential expression of 294 genes (FDR <0.05) between cows that subsequently resolved inflammation (n=10) and those that developed disease (n=20). Pathway over-representation analysis of differentially expressed genes (DEG) identified significant changes in immune-related pathways, including the NOD-like receptor signalling pathway, cytokine-cytokine receptor interaction pathway and the Toll-like receptor signalling pathway which were up-regulated in cattle that subsequently developed disease. The majority of the DEG were upregulated in cows that developed PVD, and included all genes upregulated in CYTO cows, suggesting a core inflammatory gene signature early post-partum contributes to the onset of uterine disease. This inflammatory signature was validated by qPCR in an independent group of cows (n=56) and included upregulation of pro-inflammatory genes (including TLR2, TLR4, NLRP3, IL1A, IL1B, IL8, and S100A8) at day 7 postpartum in cows that failed to resolve inflammation. Conclusions: Despite a large amount of inter-animal heterogeneity, these results suggest that excessive activation and inappropriate regulation of the inflammatory response early postpartum is a key feature of the subsequent development of uterine disease. Keywords: Endometritis, Inflammation, Transcriptome, Next generation sequencing, Dairy cattle, Uterine involution, Immune response

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Progesterone differentially affects the transcriptomic profiles of cow endometrial cell types

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