DNMT1 mediates global DNA methylation dynamics during reproductive aging in mammals

With increasing age, reproductive performance in women declines. However, the molecular mechanisms underlying ovarian aging and age-related fertility decline in women remain unclear. Proliferation, apoptosis, and steroid hormone secretion by granulosa cells (GCs) are used to determine the fate of follicles and ovarian function. First, we found that the proliferative ability of GCs in the old mice group (10-month old) was decreased and cell cycle arrest occurred compared to that in the young group (6-week old). To investigate the changes in protein modification, we studied protein acetylation between GCs of young and old mice and found that K1118, K1120, K1122, and K1124 sites of DNA methyltransferase 1 (DNMT1) were increasingly acetylated, resulting in a decrease in DNMT1 protein expression. Therefore, we performed whole-genome methylation sequencing (WGBS) of GCs between the two groups and found that the methylation levels of GCs in the old group were lower than those in the young group. Furthermore, reduction in DNMT1 expression by inhibitors in GCs resulted in cell cycle arrest. This study revealed the dynamics and importance of protein acetylation and DNA methylation in GCs during reproductive aging.