Oocyte-Specific Knockout of Histone Lysine Demethylase KDM2a Compromises Fertility by Blocking the Development of Follicles and Oocytes.

The methylation status of histones plays a crucial role in many cellular processes, including follicular and oocyte development. Lysine-specific demethylase 2a (KDM2a) has been reported to be closely associated with gametogenesis and reproductive performance, but the specific function and regulatory mechanism have been poorly characterized in vivo. We found KDM2a to be highly expressed in growing follicles and oocytes of mice in this study. To elucidate the physiological role of , the zona pellucida 3-Cre (-)/LoxP system was used to generate an oocyte conditional knockout (-; , termed cKO) model. Our results showed that the number of pups was reduced by approximately 50% in adult cKO female mice mating with wildtype males than that of the control () group. To analyze the potential causes, the ovaries of cKO mice were subjected to histological examination, and results indicated an obvious difference in follicular development between cKO and control female mice and partial arrest at the primary antral follicle stage. The GVBD and matured rates of oocytes were also compromised after conditional knockout , and the morphological abnormal oocytes increased. Furthermore, the level of 17β-estradiol of cKO mice was only 60% of that in the counterparts, and hormone sensitivity decreased as the total number of ovulated and matured oocytes decreased after superovulation. After deletion of , the patterns of H3K36me2/3 in GVBD-stage oocytes were remarkedly changed. Transcriptome sequencing showed that the mRNA expression profiles in cKO oocytes were significantly different, and numerous differentially expressed genes were involved in pathways regulating follicular and oocyte development. Taken together, these results indicated that the oocyte-specific knockout gene led to female subfertility, suggesting the crucial role of in epigenetic modification and follicular and oocyte development.