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Simple Summary  The fertility of sows is considered to be their most important economic trait, as it is critical for swine farm profitability. There are considerable differences in fertility rates among individual pigs, but the underlying molecular mechanisms remain unclear at present. The ovary is the most important reproductive organ. Folliculogenesis, ovulation, and corpus luteum formation and regression occur in the ovary, repeatedly taking place over the reproductive life and regulating mammalian reproduction. Circular RNAs (circRNAs) represent a novel type of noncoding RNA (ncRNA), which have great potential to exert effects on multiple physiological processes. In particular, some circRNAs are closely involved in reproductive processes and function as potent microRNA (miRNA) sponges to regulate target gene expression levels. In this study, ovarian circular RNAs and miRNAs associated with high and low fertility Large White sows are identified during the follicular and luteal phases of the estrous cycle, and their potential biological functions are predicted through bioinformatic analysis. Protein–protein networks and circRNA–miRNA networks are constructed based on gene expression profiles and the bioinformatic analyses, providing novel insight into fertility regulation in pigs.    Abstract  In this study, the ovarian tissues of Large White pigs were mined for novel circular RNAs (circRNAs), following which, their molecular characteristics and potential mechanisms for fertility regulation were examined. RNA sequencing was used for transcriptome analysis of ovarian follicles and corpora lutea in Large White sows with high (H) and low (L) fertility during the follicular (F) and luteal (L) phases of the estrous cycle. In total, 21,386 circRNA derived from 4535 host genes were identified. Differentially expressed circRNAs were detected in the LH vs. LL (1079) and in the FH vs. FL (1077) comparisons, and their host genes were enriched in steroid biosynthesis and forkhead box O (FOXO), thyroid hormone, cell cycle, and tumor growth factor (TGF)-beta signaling pathways. Protein–protein interaction networks were constructed on the basis of the host genes that were significantly enriched in pathways related to reproductive processes, with AKT3 and PP2CB serving as the hub genes in the networks of the LH vs. LL and FH vs. FL comparisons, respectively. The microRNA (miRNA) binding sites of the differentially expressed circRNAs were predicted, and 128 (LH vs. LL) and 113 (FH vs. FL) circRNA–miRNA pairs were identified. Finally, circRNA–miRNA negative regulatory networks were established on the basis of the gene expression profiles and bioinformatic analyses. In the current study, differentially expressed circRNAs were observed in ovarian tissues between the H and L fertility groups in both F and L phases of the estrous cycle, which suggested roles in pig fertility regulation. These findings provide new clues for elucidating fertility differences in pigs.

Ovarian Circular RNAs Associated with High and Low Fertility in Large White Sows during the Follicular and Luteal Phases of the Estrous Cycle