Ovulatory Signal-Driven H3K4me3 and H3K27ac Remodeling in Mural Granulosa Cells Orchestrates Oocyte Maturation and Ovulation

Ovulation and granulosa cell luteinization are induced by ovulatory signals, including luteinizing hormone (LH) and human chorionic gonadotropin (hCG). Histone modifications enable rapid, signal-responsive transcriptional reprogramming. However, the effects of LH/hCG-induced histone modification changes on the mural granulosa cells (MGCs) function remain to be fully elucidated. By mining public datasets we integrated transcriptomic and histone-modification profiles of MGCs across the ovulatory interval and tracked LH/hCG-driven gene expression at three time points (0, 4, and 12 h after-hCG). During oocyte maturation, the 4 h LH-surge constitutes a critical window for meiotic resumption, during which many genes display rapid transcriptional changes followed by a return to baseline levels. Early-response genes are enriched for cell locomotion, inflammatory responses, the activation of signaling pathways, and histone modifications. Furthermore, LH/hCG-induced transcriptome remodeling is highly correlated with dynamic gains or losses of H3K4me3 and H3K27ac. Notably, we discovered for the first time that H3K27ac marks super-enhancers (SEs) that regulate LH/hCG-induced transcriptional activation in MGCs. Finally, through complementary in vitro and in vivo pharmacological inhibition, we demonstrate that LH/hCG governs oocyte maturation and ovulation by reshaping the MGC transcriptome via H3K4me3- and H3K27ac-dependent chromatin remodeling. In summary, our study advances the understanding of how gonadotropins regulate MGC function and oocyte maturation through histone-modification-mediated transcriptional control.