KAT2B regulates estradiol synthesis via H3K27ac/PPARα in granulosa cells of PCOS patients

Background: Polycystic ovary syndrome (PCOS) is one of the main cause of female infertility worldwide, however the aetiology of PCOS remains elusive. In our previous microarray analysis of granulosa cells (GCs), Lysine Acetyltransferase 2B (KAT2B) was significantly highly expressed in GCs of PCOS patients. While KAT2B has been documented to participate in various biological processes, its specific role and mechanism in the pathogenesis of PCOS remain largely unknown.

Methods: We collected GCs from PCOS patients to quantify the expression levels of KAT2B and analyzed the correlation between KAT2B expression and clinical characteristics. In vitro, we used KAT2B-specific siRNA to suppress KAT2B expression in GCs and employed lentivirus to achieve KAT2B overexpression. In vivo, we established a rat model with ovary-specific overexpression of KAT2B through ovarian in situ injection of lentivirus. Furthermore, transcriptomic Sequencing was conducted to elucidate the underlying molecular mechanisms. Untargeted metabolomics analysis provided additional insights into systemic circulatory changes in the two rat models.

Results: KAT2B is abnormally overexpressed in GCs of PCOS patients, and its expression level is positively correlated with serum luteinizing hormone (LH), testosterone levels, antral follicle count (AFC), and LH/follicle-stimulating hormone (FSH) ratio, while negatively correlated with serum progesterone levels and age. In vivo experiments demonstrated that rats with ovary-specific overexpression of KAT2B exhibited PCOS-like features. Transcriptomic Sequencing of cell and rat ovarian samples indicated that the PPAR signaling pathway might be a key downstream pathway of KAT2B. Further in vitro experiments demonstrated that KAT2B regulates the transcription of PPARα by modulating H3K27ac, thereby impacting aromatase expression and estradiol synthesis. Metabolomic analysis indicated altered systemic pyruvate metabolism in rats with ovary-specific overexpression of KAT2B.

Conclusions: Our study revealed that the high expression of KAT2B in GCs might play a critical role in the development of PCOS by regulating estradiol synthesis, thereby offering a novel perspective for future investigations into the endocrine mechanisms underlying PCOS.

Estradiol synthesis; Granulosa cells; Histone acetylation; Lysine acetyltransferase 2B; Polycystic ovary syndrome.