Abstract
Polycystic ovary syndrome (PCOS) is the most common complex endocrine and metabolic disease in women of reproductive age. It is characterized by anovulatory infertility, hormone disorders, and polycystic ovarian morphology. Regarding the importance of granulosa cells (GCs) in the pathogenesis of PCOS, few studies have investigated the etiology at a single “omics” level, such as with an mRNA expression array or methylation profiling assay, but this can provide only limited insights into the biological mechanisms. Here, genome-wide DNA methylation together with lncRNA-miRNA-mRNA profiles were simultaneously detected in GCs of PCOS cases and controls. A total of 3579 lncRNAs, 49 miRNAs, 669 mRNAs, and 890 differentially methylated regions (DMR)-associated genes were differentially expressed between PCOS cases and controls. Pathway analysis indicated that these differentially expressed genes were commonly associated with steroid biosynthesis and metabolism-related signaling, such as glycolysis/gluconeogenesis. In addition, we constructed ceRNA networks and identified some known ceRNA axes, such as lncRNAs-miR-628-5p-CYP11A1/HSD17B7. We also identified many new ceRNA axes, such as lncRNAs-miR-483-5p-GOT2. Interestingly, most ceRNA axes were also closely related to steroid biosynthesis and metabolic pathways. These findings suggest that it is important to systematically consider the role of reproductive and metabolic genes in the pathogenesis of PCOS.
Highlights
Polycystic ovary syndrome (PCOS) is a life-long reproductive, neuroendocrine, and metabolic disorder that affects up to 6–15% of women of reproductive age (Risal et al, 2019)
Significant differences between the two groups were found for luteinizing hormone (LH), T, and antral follicle counts (AFC), all of which had higher levels in PCOS cases (P < 0.05)
Combining the known genes with human transcription factors (TFs), we found that the expression of FOXA1, HIF3A, and STMN1 was upregulated in PCOS granulosa cells (GCs) (Supplementary Figure 2A)
Summary
Polycystic ovary syndrome (PCOS) is a life-long reproductive, neuroendocrine, and metabolic disorder that affects up to 6–15% of women of reproductive age (Risal et al, 2019). In addition to the above reproductive disorders, PCOS is often accompanied by metabolic abnormalities, such as insulin resistance (IR). Studies have shown that the abnormal ovarian hormone production is mainly attributed to the hypertrophy of follicular theca cells and the altered expression of key steroid biosynthesis enzymes in GCs (Aste et al, 1998). Previous studies have shown that cumulus and mural GCs contribute to the process of oocyte maturation by tight regulation and controlled changes in steroid hormones in the pathogenesis of PCOS (Holesh et al, 2020). Oocytes lack the capacity to carry out some metabolic processes, such as glycolysis and amino acid uptake. They rely on GCs to deliver nutrients and remove waste. The metabolic profile of GCs is associated with the fate of their accompanying oocyte (Gioacchini et al, 2018; Yilmaz et al, 2018; Fontana et al, 2020)
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