Reduced DNMT1 expression associated with TP53 promoter hypomethylation mediate enhanced granulosa cell senescence during ovarian aging.

BACKGROUND

The effects of granulose cell (GC) senescence on premature ovarian insufficiency/premature ovarian failure have been extensively examined, the association between GC senescence and ovarian aging remains to be clarified.

METHODS

Human and mouse GCs from young/control and old/advanced maternal age (AMA) groups were collected, and GC senescence was determined. The role of the DNMT1-p53 axis in GC senescence during ovarian aging was examined and validated in a KGN cell senescence model.

RESULTS

SA-beta-gal-positive GCs were significantly increased in the AMA group, accompanied by activation of the p53-p21 pathway, which was also found in GCs from aged mice and HO-induced senescent KGN cells. Pyrosequencing methylation analysis revealed that increased expression of p53 was associated with decreased average methylation levels of CpG sites (-1031, -1019, -1012 and -1008) within the promoter CpG island in senescenct GCs and KGN cells. We further found that decreased DNA-methyltransferase 1 (DNMT1) expression was responsible for the reduced methylation levels of the CpG sites.

CONCLUSION

Decreased DNMT1 with hypomethylation of the CpG sites within the promoter CpG island in GCs is involved in ovarian aging.