Nuclear lncRNA NORSF reduces E2 release in granulosa cells by sponging the endogenous small activating RNA miR-339

Background: Functioning as a competing endogenous RNA (ceRNA) is the main action mechanism of most cytoplasmic lncRNAs. However, it is not known whether this mechanism of action also exists in the nucleus. Results: We identified four nuclear lncRNAs that are presented in granulosa cells (GCs) and were differentially expressed during sow follicular atresia. Notably, similar to cytoplasmic lncRNAs, these nuclear lncRNAs also sponge miRNAs in the nucleus of GCs through direct interactions. Furthermore, NORSF (non-coding RNA involved in sow fertility), one of the nuclear lncRNA acts as a ceRNA of miR-339. Thereby, it relieves the regulatory effect of miR-339 on CYP19A1 encoding P450arom, a rate-limiting enzyme for E2 synthesis in GCs. Interestingly, miR-339 acts as a saRNA that activates CYP19A1 transcription and enhances E2 release by GCs through altering histone modifications in the promoter by directly binding to the CYP19A1 promoter. Functionally, NORSF inhibited E2 release by GCs via the miR-339 and CYP19A1 axis. Conclusions: Our findings highlight an unappreciated mechanism of nuclear lncRNAs and show it acts as a ceRNA, which may be a common lncRNA function in the cytoplasm and nucleus. We also identified a potential endogenous saRNA for improving female fertility and treating female infertility.