Excess bile acid impairs oocyte maturation through H1.2-mediated chromatin and epigenetic remodeling

Abstract Oocyte development requires precise coordination between metabolic and epigenetic programs, yet how metabolic disturbances affect chromatin regulation remains unclear. Here, we identify a mechanistic link between bile acid metabolism and oocyte maturation. Excess cholic acid (CA) impairs meiotic progression and spindle assembly, accompanied by a marked depletion of linker histone H1.2. Quantitative proteomics and functional assays reveal that H1.2 insufficiency drives chromatin decompaction and loss of H3K27me3, leading to defective meiotic apparatus assembly and increased aneuploidy. CUT&Tag profiling further identifies genome-wide redistribution of H3K27me3 at promoters of WNT signaling and kinase-regulatory genes. Restoring H1.2 expression reinstates both chromatin organization and meiotic fidelity in CA-treated oocytes. These findings suggest that H1.2 is a chromatin-associated factor associated with oocyte quality and that excess cholic acid compromises oocyte competence, at least in part, through H1.2-mediated epigenetic remodeling. This metabolic-epigenetic coupling provides mechanistic insight into infertility associated with cholestasis, polycystic ovary syndrome, and other metabolic disorders.