Effects of androgen excess-related metabolic disturbances on granulosa cell function and follicular development
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA794860 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17455712_1.fastq.gz | Fastqsanger.gz | |||
| SRR17455712_2.fastq.gz | Fastqsanger.gz | |||
| SRR17455713_1.fastq.gz | Fastqsanger.gz | |||
| SRR17455713_2.fastq.gz | Fastqsanger.gz | |||
| SRR17455714_1.fastq.gz | Fastqsanger.gz |
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Project description:The purpose of this study was to explore the difference in transcript profiles between the ovarian granulosa cells from healthy women and women with polycystic ovary syndrome (PCOS). Quantitative reverse transcription polymerase chain reaction (qRT–PCR) was applied to validate results of RNA sequencing in the present study.
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Project description:Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease in women of reproductive age. Ovarian dysfunction including abnormal steroid hormone synthesis and follicular arrest play a vital role in PCOS pathogenesis. Hyperandrogenemia is one of the important characteristics of PCOS. However, the mechanism of regulation and interaction between hyperandrogenism and ovulation abnormalities are not clear. To investigate androgen-related metabolic state in granulosa cells of PCOS patients, we identified the transcriptome characteristics of PCOS granulosa cells by RNA-seq. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes (DEGs) revealed that genes enriched in lipid metabolism pathway, fatty acid biosynthetic process and ovarian steroidogenesis pathway were abnormally expressed in PCOS granulosa cells in comparison with that in control. There are close interactions among these three pathways as identified by analysis of the protein-protein interaction (PPI) network of DEGs. Furthermore, in vitro mouse follicle culture system was established to explore the effect of high androgen and its related metabolic dysfunction on follicular growth and ovulation. RT-qPCR results showed that follicles cultured with dehydroepiandrosterone (DHEA) exhibited decreased expression levels of cumulus expansion-related genes (Has2, Ptx3, Tnfaip6 and Adamts1) and oocyte maturation-related genes (Gdf9 and Bmp15), which may be caused by impaired steroid hormone synthesis and lipid metabolism, thus inhibited follicular development and ovulation. Furthermore, the inhibition effect of DHEA on follicle development and ovulation was ameliorated by flutamide, an androgen receptor (AR) antagonist, suggesting the involvement of AR signaling. In summary, our study offers new insights into understanding the role of androgen excess induced granulosa cell metabolic disorder in ovarian dysfunction of PCOS patients.
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Project description:Excessive androgen production is a hallmark of human and bovine ovarian disorders, and our lab has identified a naturally-occurring bovine model with excess follicular fluid androstenedione (A4) without a proportional estrogen increase. Granulosa cell populations from both the control, Low A4 follicles and the abnormal, High A4 follicles were isolated. Total RNA was extracted from those granulosa cells and submitted to the University of Nebraska Medical Center Microarray Core Facility for transcriptome quantification using Affymetrix Bovine GeneChip Gene 1.0 ST Arrays. The orignal Affymetrix .CEL files and the normalized linear expression data are included in this submission.
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Project description:Proteomic Analysis of Healthy and Atretic Porcine Follicular Granulosa Cells
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Project description:<p>Polycystic ovary syndrome (PCOS) is the primary cause of female infertility. Growing evidence suggests that dysregulation of amino acid metabolism plays a significant role in the onset and progression of PCOS. However, the underlying mechanism remains unclear. In this study, we conducted targeted metabolite profiling of human follicular fluid (FF) and granulosa cells (GCs). A significant increase in glutamine (Gln) uptake was observed in patients with hyperandrogenic-PCOS (HA-PCOS), mediated by the upregulation of SLC1A5, a specific Gln transporter. We subsequently confirmed that androgen excess primarily activates SLC1A5 expression. Furthermore, Slc1a5 overexpression in female mice induced PCOS-like phenotypes, including hyperandrogenism and abnormal follicle development. Additionally, the pharmacological blockade of SLC1A5 provided reproductive benefits to mice exhibiting PCOS-like symptoms. Mechanistically, we found that elevated flux of Gln-derived α-ketoglutarate (α-KG) enhanced HDAC5 expression and suppressed acetylation on histone 3 lysine residue 14 and lysine residue 56. The reduction in acetylation level correlated with the downregulation of several genes related to folliculogenesis, including CYP19A1, thereby exacerbating androgenic homeostasis imbalance. These findings indicate that androgen-induced aberrant Gln uptake via SLC1A5 is crucial for the development and progression of PCOS, suggesting pharmacological blockade of SLC1A5 as a potential therapeutic strategy for PCOS patients.</p>
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Project description:The lipid metabolism of granulosa cells plays a pivotal role in the development of goose follicles. However, the mechanisms by which lipid droplet-associated proteins regulate lipid droplets and influence cellular lipid metabolism remain poorly understood. To address this, our study systematically identified lipid droplet-associated proteins in goose follicular granulosa cells and analyzed these proteins at five distinct time points, in both pre-hierarchical granulosa cells and hierarchical granulosa cells, thereby obtaining relevant information on lipid droplet-associated proteins.
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Project description:Polycystic ovary syndrome (PCOS) is the primary cause of female infertility. Growing evidence suggests that dysregulation of amino acid metabolism plays a significant role in the onset and progression of PCOS. However, the underlying mechanism remains unclear. In this study, we conducted targeted metabolite profiling of human follicular fluid (FF) and granulosa cells (GCs). A significant increase in glutamine (Gln) uptake was observed in patients with hyperandrogenic-PCOS (HA-PCOS), mediated by the upregulation of SLC1A5, a specific Gln transporter. We subsequently confirmed that androgen excess primarily activates SLC1A5 expression. Furthermore, Slc1a5 overexpression in female mice induced PCOS-like phenotypes, including hyperandrogenism and abnormal follicle development. Additionally, the pharmacological blockade of SLC1A5 provided reproductive benefits to mice exhibiting PCOS-like symptoms. Mechanistically, we found that elevated flux of Gln-derived α-ketoglutarate (α-KG) enhanced HDAC5 expression and suppressed acetylation on histone 3 lysine residue 14 and lysine residue 56. The reduction in acetylation level correlated with the downregulation of several genes related to folliculogenesis, including CYP19A1, thereby exacerbating androgenic homeostasis imbalance. These findings indicate that androgen-induced aberrant Gln uptake via SLC1A5 is crucial for the development and progression of PCOS, suggesting pharmacological blockade of SLC1A5 as a potential therapeutic strategy for PCOS patients.
2025-04-14 | MTBLS12371 | MetaboLights
Project description:Considering the well-documented importance of androgens in the female reproductive system and particularly in maintenance of the ovarian follicular reserve, follicle growth and granulosa cell proliferation, we hypothesized that activation of the androgen receptor in granulosa cells with DHT induces significant changes in gene transcription. To determine the AR-regulated gene transcriptome in mouse granulosa cells, we treated female mice aged 18 weeks (n=5) with an introperitoneal injection of dihydrotestosterone (DHT, 29 mcg) in a vehicle of 90% sesame oil and 10% ethanol in a total volume of 100 microliters. 18 hours later, granulosa cells were harvested and mRNA was isolated for RNA sequencing. Surprisingly, no genes were differentially expressed in the granulosa cells obtained from DHT-treated compared with vehicle-treated mice. We then assessed the AR-regulated transcriptome in DHT-treated human granulosa-derived KGN cells. After 24 hours of serum starvation, KGN cells were treated with 25 nM DHT or ethanol for 12 hours in five independent experiments, then RNA was extracted for RNA sequencing. In paired analysis to eliminate inter-experimental variability, 173 genes were differentially expressed in DHT-treated compared with vehicle-treated cells. Of these, 125 genes were upregulated by DHT and 48 genes were downregulated by DHT. However, the fold change in expression was very small (ranging from 0.87 to 1.37, DHT vs vehicle). Although these differences were statistically signficant in paired analysis, they are unlikely to be of biological significance due to such small fold changes in expression. We conclude that AR likely has negligible gene-transcription activity in granulosa cells. Importantly, these experiments were not designed to capture any changes in non-coding RNAs.
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Project description:Cellular dedifferentiation signifies the withdrawal of cells from a specific differentiated state into a ‘stem cell’-like undifferentiated state. However, the mechanism of dedifferentiation remains obscure. We showed that follicular granulosa cells (GC), which have distinct functions in vivo, can dedifferentiate during culture in vitro and acquire multipotency. We investigated the dedifferentiation of GC using global gene expression analyses.
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Project description:Human granulosa cells are follicular cells surrounding the oocyte. Human granulosa cells are retrieved during in vitro fertilization a process where patients undergo hormonal stimulation including FSH and LH/hCG stimulation. Under the influence of the luteinizing hormone (LH) a process called luteinization they differentiate to luteal cells and contribute to the corpus luteum. Therefore, this cellular system is a good model for human corpus luteum (CL). To study processes within the human CL, IVF-derived GCs from patients were cultured for two to five days and then analyzed with mass spectrometry based shotgun proteomics.
2019-03-07 | PXD010658 | Pride