The Methylation Regulator PRDM6 Confers Protection Against Polycystic Ovary Syndrome: Evidences from Bioinformatics and Experimental Approaches.

Abstract

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an unclear epigenetic basis. This study sought to identify critical methylation regulators implicated in PCOS progression and evaluate their therapeutic potential through comprehensive experimental validation. Bioinformatics analysis was performed to screen differentially expressed genes (DEGs) associated with PCOS and methylation regulators from public databases. Intersection analysis revealed PRDM6 as a key methylation regulator among 177 PCOS-related DEGs and 175 known methylation regulators. Further in silico prediction identified 16 PRDM6-correlated DEGs harboring potential post-translational modification (PTM) sites, with functional enrichment analysis linking them to the cAMP signaling pathway, notably involving RAC3, FXYD1, and SSTR2. To validate these findings, we established in vivo PCOS models using dehydroepiandrosterone-induced rats and in vitro models to mimic PCOS-associated insulin resistance using insulin-induced granulosa cells. In the rodent model, PRDM6 expression was significantly downregulated, while lentivirus-mediated PRDM6 overexpression restored serum sex hormone levels (measured by ELISA) and ameliorated ovarian histopathological abnormalities (assessed via hematoxylin-eosin staining). In vitro, PRDM6 upregulation in granulosa cells attenuated insulin-induced hyperproliferation (evaluated by CCK-8 and EdU assays) and suppressed pro-inflammatory responses (quantified by ELISA). Collectively, these results demonstrated that PRDM6 serves as a pivotal methylation regulator in PCOS pathogenesis, with therapeutic relevance in mitigating hormonal dysregulation, ovarian dysfunction, aberrant granulosa cell proliferation, and inflammation. This study provides novel insights into the epigenetic mechanisms underlying PCOS and highlights PRDM6 as a potential therapeutic target.