Histone acetyltransferase KAT8 is essential for mouse oocyte development by regulating ROS levels

Abstract

Proper oocyte development is crucial for female fertility and requires timely and accurate control of gene expression. K (lysine) acetyltransferase 8 (KAT8), an important component of the X chromosome dosage compensation system in <i>Drosophila</i>, regulates gene activity by acetylating histone H4 preferentially at lysine 16. To explore the function of KAT8 during mouse oocyte development, we crossed <i>Kat8^flox/flox</i> mice with <i>Gdf9-Cre</i> mice to specifically delete <i>Kat8</i> in oocytes. Oocyte <i>Kat8</i> deletion resulted in female infertility, with follicle development failure in the secondary and preantral follicle stages. RNA-seq analysis revealed that <i>Kat8</i> deficiency in oocytes results in significant downregulation of antioxidant genes, with a consequent increase in reactive oxygen species. Intraperitoneal injection of the antioxidant N-acetylcysteine rescued defective follicle and oocyte development resulting from <i>Kat8</i> deficiency. Chromatin immunoprecipitation assays indicated that KAT8 regulates antioxidant gene expression by direct binding to promoter regions. Taken together, our findings demonstrate that KAT8 is essential for female fertility by regulating antioxidant gene expression and identify KAT8 as the first histone acetyltransferase with an essential function in oogenesis.