Abstract
Transforming growth factor-β1 (TGF-β1) 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-β1 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-β1 3′-UTR activity. Interestingly, miR-2337 induces, not reduces the transcription and production of TGF-β1 in granulosa cells (GCs). Mechanistically, miR-2337 enhances TGF-β1 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-β1-mediated activity of the TGF-β signaling pathway and GC apoptosis. Taken together, our findings identify miR-2337 as an endogenous small activating RNA (saRNA) of TGF-β1 in GCs, while miR-2337 is identified as a small activator of the TGF-β signaling pathway which is expected to be a new target for rescuing GC apoptosis and treating low fertility.
Highlights
Transforming growth factor-β1 (TGF-β1) is an essential ligand of the TGF-β signaling pathway [1, 2]
The number of piglets born alive (NBA) of sows with the GG/GG/CC genotype was 13.06, which is 0.39 more than that of the AG/AG/AC genotype and 0.33 more than that of the AA/AA/AA genotype, but the difference was not significant (Fig. 1F). This trend is consistent with the results in another Yorkshire population, in which the total number of piglets born (TNB) of sows with the GG/GG genotype for c.1583A > G and c.1587A > G was significantly higher than that of the AA/AA genotype [24]. These data indicate an important role that TGF-β1 3′-UTR variants play on the reproductive performance of Yorkshire sows
TGF-β1 is highly expressed in the reproductive system, which has been shown to be strongly related to female fertility by controlling important events in reproductive cycle, such as, ovulation, fertilization, implantation, early embryo development, and pregnancy [7, 28,29,30]
Summary
Transforming growth factor-β1 (TGF-β1) is an essential ligand of the TGF-β signaling pathway [1, 2]. Increasing evidence has demonstrated that TGF-β1 is closely involved in ovarian functions, including follicular development [8, 9], ovulation [10], steroid production [11, 12], and GC apoptosis [13]. In female mice with knock out of the TGF-β1 gene, ovarian function was destroyed and the oocytes decreased by 40% [7]. TGF-β1 promotes estradiol release from mouse GCs [14], and inhibits the production of progesterone and prostaglandin E2 in the corpus luteum from bovine ovaries [15]. Our recent report demonstrated that TGF-β1 can inhibit porcine GC apoptosis [13]. TGF-β1 is involved in female fertility, including fertilization, early embryo development and litter size [2, 7]
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