Pituitary-secreted luteinizing hormone (LH) induces ovulation by activating an extracellular regulated kinase 1/2 (ERK1/2) cascade. However, little is known regarding the ERK1/2 downstream effectors that are involved in regulating rapid, transient expression of LH-target gene in ovulatory follicles. By comparing the gene expression profiles of LH-stimulated wild type with ERK1/2-deleted ovarian granulosa cells (GCs), we identified Cited4 as a previously unknown LH target gene during ovulation. LH induced Cited4 expression in pre-ovulatory follicles in an ERK1/2-dependent manner. CITED4 formed an endogenous protein complex and docked on the promoters of LH and ERK1/2 target genes. Both CITED4 expression and CBP acetyltransferase activity leading to histone acetylation were indispensable for LH-induced ovulation-related events. LH induced dynamic histone acetylation changes in pre-ovulatory GCs, including the acetylation of histone H2B (Lys5) and H3 (Lys9). This was essential for the rapid responses and dramatic increases of LH target gene expressions by the ordered activation of ERK1/2 and CITED4-CBP. In addition, histone deacetylases (HDACs) antagonized CITED4-CBP to turn off expression of these genes after exposure to LH. Thus, we determined that CITED4 was a novel LH and ERK1/2 target for triggering ovulation. These results support the proposition that LH induces rapid, significant gene expression in pre-ovulatory follicles by modulating histone acetylation status.
Keywords: CITED4; MAPK signaling pathway; follicle; granulosa cell; ovulation.
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