Abstract
The ovulatory luteinizing hormone (LH) surge induces rapid changes of gene expression and cellular functions in granulosa cells (GCs) undergoing luteinization. However, it remains unclear how the changes in genome-wide gene expression are regulated. H3K4me3 histone modifications are involved in rapid alteration of gene expression. In this study, we investigated genome-wide changes of transcriptome and H3K4me3 status in mouse GCs undergoing luteinization. GCs were obtained from mice treated with equine chorionic gonadotropin (eCG) before, 4 h and 12 h after human (h)CG injection. RNA-sequencing identified a number of up- and down-regulated genes, which could be classified into eight patterns according to the time-course changes of gene expression. Many genes were transiently up- or down-regulated at 4 h after hCG stimulation. Gene ontology terms associated with these genes included steroidogenesis, ovulation, COC expansion, angiogenesis, immune system, ROS metabolism, inflammatory response, metabolism and autophagy. The cellular functions of DNA repair and cell growth were newly identified as being activated during ovulation. ChIP-sequencing revealed a genome-wide and rapid change of H3K4me3 during ovulation. Integration of transcriptome and H3K4me3 data identified many H3K4me3-associated genes that are involved in steroidogenesis, ovulation, COC expansion, angiogenesis, inflammatory response, immune system, ROS metabolism, lipid and glucose metabolism, autophagy, and regulation of cell size. The present results suggest that genome-wide changes in H3K4me3 after the LH surge are associated with rapid changes in gene expression in GCs, which enables GCs acquire a lot of cellular functions within a short time that are required for ovulation and luteinization.