miR-2337 induces TGF-β1 production in granulosa cells by acting as an endogenous small activating RNA

Transforming growth factor-beta 1 (TGF-beta 1) is essential for ovarian function and female fertility in mammals. Herein, we identified three completely linked variants, including two known variants referred to as c.1583A>G and c.1587A>G and the novel variant c.2074A>C in the porcine TGF-beta 1 3 ' -UTR. An important role of these variants in Yorkshire sow fertility was revealed. Variants c.1583A>G and c.1587A>G were located at the miRNA response element (MRE) of miR-2337 and affected miR-2337 regulation of TGF-beta 1 3 ' -UTR activity. Interestingly, miR-2337 induces, not reduces the transcription and production of TGF-beta 1 in granulosa cells (GCs). Mechanistically, miR-2337 enhances TGF-beta 1 promoter activity via the MRE motif in the core promoter region and alters histone modifications, including H3K4me2, H3K4me3, H3K9me2, and H3K9ac. In addition, miR-2337 controls TGF-beta 1-mediated activity of the TGF-beta signaling pathway and GC apoptosis. Taken together, our findings identify miR-2337 as an endogenous small activating RNA (saRNA) of TGF-beta 1 in GCs, while miR-2337 is identified as a small activator of the TGF-beta signaling pathway which is expected to be a new target for rescuing GC apoptosis and treating low fertility.

Automated summary

The discovered miR-2337 plays a significant role in the fertility of sows by enhancing TGF-beta 1 promoter activity and altering histone modifications, controlling TGF-beta 1-mediated signaling pathway activity and GC apoptosis.