MicroRNA-127-5p impairs function of granulosa cells via HMGB2 gene in premature ovarian insufficiency

Distinct microRNA (miRNA) profiles have been reported in premature ovarian insufficiency (POI), but their functional relevance in POI is not yet clearly stated. In this study, aberrant expressions of miR-127-5p and high mobility group box 2 (HMGB2) were observed by microarrays in granulosa cells (GCs) from biochemical POI (bPOI) women and further confirmed by a quantitative reverse-transcription polymerase chain reaction. Immortalized human granulosa cell line and mouse primary ovarian GCs were used for functional validation. Orthotopic mouse model was established to examine the role of miR-127-5p in vivo. Finally, the expression of miR-127-5p was measured in the plasma of bPOI women. The receiver operating characteristic curve analysis was performed to determine the indicative role of miR-127-5p for ovarian reserve. Results showed the upregulation of miR-127-5p was identified in GCs from bPOI patients. It inhibited GCs proliferation and impaired DNA damage repair capacity through targeting HMGB2, which was significantly downregulated in GCs from the same cohort of cases. miR-127-5p was confirmed to attenuate DNA repair capability via HMGB2 in mouse ovary in vivo. Intriguingly, the upexpression of miR-127-5p was also detected in plasma of bPOI individuals, suggesting that miR-127-5p could be a promising indicator for bPOI. Taken together, our results discovered the deleterious effects of miR-127-5p on GCs function and its predictive value in POI process. The target gene HMGB2 could be considered as a new candidate for POI. This study highlights the importance of DNA repair capacity for ovarian function and sheds light on the epigenetic mechanism in the pathogenicity of POI.