Oxidative stress controls lncRNA-mediated granulosa cell functions in a FoxO1-dependent manner

Abstract

Background Oxidative stress (OS) is intensely involved in female low fertility by altering the multi-omics such as transcriptome, miRome, and lncRNome in follicular cells and follicular fluid. However, the mechanism by which OS affects multi-omics dynamics is largely unknown. Here, we report that OS induces lncRNome dynamics in sow granulosa cells (sGCs) partially depending on the transcription factor activity of its effector FoxO1. Results 2283 putative FoxO recognition elements (FREs) were identified in the promoters of 394 lncRNAs, accounting for 91.20% (394/432) of the lncRNAs stimulated by OS. ChIP and reporter assays showed that effector FoxO1 mediates OS regulation of the transcription activity of lncRNAs in a transcription factor activity-dependent manner. In sGCs, OS induces the transcription of NORSF, a nuclear lncRNA involved in sGCs functions and its mediated cell apoptosis via FoxO1. Furthermore, FoxO1 was identified as a transcription activator of NORSF in sGCs by interacting with the FRE motif of its promoter. Meanwhile, OS reduces the transcription of CYP19A1, which encodes an essential enzyme for estrogen synthesis, and 17β-estradiol (E2) release by sGCs via the FoxO1 and NORSF axis. Phenotypically, transcriptional dysregulation of NORSF transcription caused by two novel adjacent transitions in the promoter leads to decreased sow fertility. Conclusion These results suggest a model of OS-stimulated lncRNome dynamics of sGCs, and a new signaling pathway of OS influences sGC functions and sow fertility.