FRI388 Follicle-Stimulating Hormone And Salt-inducible Kinases Crosstalk On The Regulation Of Genome-wide Gene Expression In Human Granulosa Cumulus Cells

Abstract

Abstract Disclosure: E. Hayes: None. R. Filzen: None. M. Rodriguez Esquivel: None. N. Winston: None. M. Fierro: None. S. Sana: None. C.O. Stocco: Grant Recipient; Self; NIH R01HD097202. Infertility affects approximately 15% of couples, 40% are due to ovulatory defects. Successful ovulation requires the timely and tight regulation of folliculogenesis by gonadotropins, more crucially, follicle-stimulating hormone (FSH), which is needed to form preovulatory follicles. However, the mechanisms governing folliculogenesis are incompletely understood. We previously showed that salt inducible kinases (SIKs) are critical regulators of female fertility. Specifically, knockout of SIK2 enhances ovulation, whereas deletion of SIK3 results in anovulation and premature ovarian failure. At the molecular level, SIK2, but not SIK3, attenuates the expression of FSH-induced steroidogenic genes. This report aimed to outline the genome-wide effect of SIK inhibition on gene expression in the presence or absence of FSH. Here, we treated human cumulus cells with a SIK inhibitor, HG-9-91-01 (HG), FSH, or their combination. We then performed RNA sequencing and identified 3,472 differentially expressed genes (DEGs) across treatment groups. Interestingly, 498/646 (77%) of DEGs in FSH-treated cells were also identified as DEGs in HG-treated cells. Further, HG + FSH resulted in 865 DEGs not differentially regulated by FSH or HG alone. Analysis of DEGs by Gene Set Enrichment Analysis (GSEA) revealed top enriched gene ontology terms including processes related to the extracellular matrix, steroid hormone biosynthesis, PI3K-Akt signaling, and cAMP signaling. The data suggest that SIK activity profoundly affects gene expression in human granulosa cells, likely via regulation of FSH signaling and other mechanisms. These findings provide new insights and directions for investigating the mechanisms by which SIKs regulate ovarian function and fertility. Presentation: Friday, June 16, 2023