The 12th International Symposium on 3D Genomics

Polycystic ovary syndrome (PCOS) is a prevalent reproductive and metabolic disorder characterized by hyperandrogenism, ovulatory dysfunction, and ovarian metabolic abnormalities. However, the mechanisms by which metabolic perturbations are translated into stable epigenetic and three-dimensional (3D) genome alterations remain insufficiently defined. Here, we present evidence that metabolic dysregulation drives pathogenic chromatin remodeling in PCOS, with a primary focus on histone lactylation-mediated 3D genome reorganization. Using integrative multi-omics approaches, we identified nuclear pyruvate kinase M2 (nPKM2) as a key metabolic-epigenetic regulator in PCOS ovaries. Increased nuclear accumulation of PKM2 was associated with elevated histone lactylation, particularly H3K9la and H3K18la, and accompanied by extensive 3D chromatin remodeling, including compartment switching, topologically associated domain fusion, and the establishment of new enhancer-promoter interactions. These structural alterations were linked to activation of steroidogenic genes, including CYP11A1 and CYP17A1, thereby promoting androgen excess. Pharmacological inhibition of PKM2 nuclear translocation ameliorated PCOS-like phenotypes in mice and partially restored the transcriptional landscape toward a normal state. We further found that nicotinamide N-methyltransferase (NNMT), overexpressed in PCOS granulosa cells, as a metabolic-epigenetic switch that drives disease progression. NNMT overexpression in PCOS reduced H3K27me3, derepressed RARB, and enhanced androgen biosynthesis. Second, integration of single-cell multi-omics with spatial transcriptomics enabled construction of a spatial chromatin accessibility atlas of the PCOS mouse ovary, we found increased NFE2L2 motif activity and implicating NFE2L2-associated programs in altered 3D genome organization. Collectively, these findings support a model in which metabolic abnormalities reshape the ovarian epigenome and 3D genome architecture to drive androgenic reprogramming in PCOS, and indicate epigenome as potential therapeutic targets for PCOS.