O-130 Dysregulated Epigenetic Reprogramming during Pre-Implantation Development of Embryos from Patients with Polycystic Ovary Syndrome

Abstract Study question How Abnormal Epigenetic Reprogramming Prior to Embryo Implantation Contributes to the Onset and Intergenerational Inheritance of Polycystic Ovary Syndrome (PCOS)? Summary answer PCOS embryos exhibit dysregulated epigenetic reprogramming, including H3K4me3, H3K27me3, H3K9me3, and DNA methylation, which are associated with abnormal gene expression and inherited anomalies from oocytes. What is known already PCOS is a leading cause of infertility, with familial aggregation and unclear intergenerational inheritance mechanisms. Abnormal epigenetic regulation in early embryonic development has been linked to disease inheritance. Study design, size, duration This was a comparative study analyzing the transcriptome and epigenome of oocytes and preimplantation embryos collected from 133 PCOS patients and 95 non-PCOS infertile women. Participants/materials, setting, methods Oocytes and embryos from PCOS and non-PCOS infertile women were analyzed using ultra-low-input sequencing techniques, including Smart-seq2, CUT&RUN, and WGBS, to identify transcriptomic and epigenomic abnormalities. Main results and the role of chance PCOS embryos demonstrated significant dysregulation of zygotic genome activation genes, epigenetic regulators, PCOS-linked genes, and retrotransposons during preimplantation development. These anomalies were linked to abnormal epigenetic reprogramming, particularly in histone modifications (H3K4me3, H3K27me3, H3K9me3) and DNA methylation, with a substantial portion inherited from PCOS oocytes. Treatment with PRC2 complex inhibitors effectively rescued abnormal gene expression, indicating a critical role of these epigenetic modifications in driving the observed abnormalities. Key regulatory factors associated with these epigenetic disruptions were identified. Statistical analyses confirmed the robustness of the findings, minimizing the role of chance. Limitations, reasons for caution The study’s findings are based on in vitro analyses of oocytes and preimplantation embryos, which may not fully capture in vivo processes. Further research is needed to validate the long-term effects of these epigenetic abnormalities on post-implantation development and the health of offspring. Wider implications of the findings This study highlights a direct link between aberrant epigenetic reprogramming in early embryos and the intergenerational inheritance of PCOS. These findings provide a foundation for developing targeted therapeutic interventions and risk assessment strategies for PCOS in offspring, offering new avenues for prevention and treatment. Trial registration number No