SMARCA2 is regulated by NORFA/miR-29c, a novel pathway related to female fertility, controls granulosa cell apoptosis

Abstract

SMARCA2, an evolutionarily conserved catalytic ATPase subunit of the SWI/SNF complexes, has been implicated in development and diseases. However, its role in mammalian ovarian function and female fertility is unknown. Here, we identified and characterized the 3’-UTR of porcine SMARCA2 gene, and a novel adenylate number variation was identified. Notably, this mutation is significantly associated with sow litter size traits and SMARCA2 levels by influencing the stability of SMARCA2 mRNA in ovarian granulosa cells (GCs). Immunohistochemistry and functional analysis show that SMARCA2 is involved in the regulation of follicular atresia by inhibiting GC apoptosis. In addition, miR-29c, a pro-apoptotic factor, was identified as a functional miRNA that targets SMARCA2 in GCs, and mediated NORFA/SMAD4 axis regulation of SMARCA2 expression. Although a potential miR-29c responsive element was identified within NORFA, NORFA negatively regulates miR-29c expression not through being a competing endogeneous RNA. In conclusion, our findings demonstrate that SMARCA2 is a candidate gene for sow litter size traits as it regulates follicular atresia and GC apoptosis; additionally, we have defined a novel candidate pathway for sow fertility, NORFA/TGFBR2/SMAD4/miR-29c/SMARCA2 pathway.