Unravelling the molecular landscape of polycystic ovary syndrome (PCOS) and role of inflammation through transcriptomics analysis of human ovarian granulosa cells.

Abstract

Background: Polycystic ovary syndrome (PCOS) is a common metabolic problem in women of reproductive age that can lead to infertility and other metabolic disorders. Recent evidence indicates that inflammation might be one of the contributing factors in PCOS progression. However, there is a lack of information on the regulation of inflammatory genes in PCOS. Therefore, the aim of the study is to investigate the role of inflammation-associated genes and pathways in relation to PCOS.

Method: The bulk RNA-seq data of granulosa cells of human ovaries of PCOS-affected and healthy women were analyzed to evaluate the inflammatory regulation in PCOS. After quality trimming, the raw RNA-seq data were aligned to the human genome, and gene expression was quantified using featureCounts with Ensembl annotation. Further, downstream analyses of the resulting count matrix were performed in R Studio, where differentially expressed genes (DEG) were identified and CO-DEG analysis was performed.

Results: The study identifies the various differentially expressed inflammatory genes in the case of PCOS such as SPI1, HSPB1, MNDA, and ITGA. These DEG are closely associated with the activation of inflammatory responses, i.e., activation of lymphocytes and leukocytes, leukocyte migration and mononuclear cell proliferation, stimulating binding of various cytokines, immunoglobulins, and chemokines. PCOS group also exhibited an increased expression of androgen-mediated genes (SPI1 and ETS transcription factors) and genes associated with hyperlipidemia and insulin resistance (TNFRSF1B). Further, KEGG pathway enrichment analysis revealed significant upregulation of various pathways (autophagy, endocytosis) in the PCOS group. In addition, network analysis (cnetplot) of the top 10 KEGG GSEA pathways also highlights the key pathways in the PCOS group such as SNARE complex assembly pathway, SNAP-25, nucleophagy, and regulation of mast cell activation.

Conclusion: Therefore, the study highlights that inflammation is a major effector in PCOS, which also fuels obesity, an independent effector that further worsens the PCOS condition. In addition, the genes related to hyperandrogenism, hyperlipidemia, and insulin resistance were also overexpressed in PCOS, exacerbating the condition.