Insights from two independent transcriptomic studies of the bovine corpus luteum during pregnancy

Lay Summary Reproductive efficiency is necessary for the financial and environmental sustainability of cattle production. A critical component of this efficiency is the maintenance of pregnancy. The corpus luteum (CL) is a transient ovarian endocrine gland that produces progesterone-the hormone that maintains pregnancy in all mammals. With each new reproductive cycle, a new CL is formed from the remnant of the ovulatory follicle, and at the end of each cycle, in the absence of a pregnancy, the CL regresses in response to prostaglandin F2 alpha from the uterus. In contrast, in the presence of a pregnancy, the CL is rescued from regression by the embryo, in a process known as maternal recognition of pregnancy. The embryo is known to alter uterine function, but its effect on the CL has remained a mystery until recent years. In this study, we compared two independent studies of global changes in the CL of pregnancy, to identify the most important luteal changes that occur during early pregnancy. We confirmed evidence for embryonic signaling to the CL and generated a list of candidate genes that are the likeliest regulators of changes to luteal function in early pregnancy. This list includes regulators of tissue integrity and inflammation. Several recent studies have used transcriptomics to investigate luteal changes during the maternal recognition of the pregnancy period in ruminants. Although these studies have contributed to our understanding of luteal function during early pregnancy, few attempts have been made to integrate information across these studies and distinguish key luteal transcripts or functions that are repeatably identified across multiple studies. Therefore, in this study, two independent studies of the luteal transcriptome during early pregnancy were combined and compared. In the first study, corpora lutea (CL) from day 20 of pregnancy were compared with CL collected on day 14 of pregnancy, prior to embryonic signaling. The cattle were nonlactating. In the second study, CL from day 20 of pregnancy were compared with CL collected from day 20 cyclic cattle that had been confirmed as not yet undergoing luteal regression. These were lactating cattle. Three methods were used to compare these two datasets, to identify key luteal regulators. In the first method, all transcripts with Benjamini-Hochberg-adjusted P-value (Q value) < 0.05 in both datasets were considered. This yielded 22 transcripts, including several classical interferon-stimulated genes, as well as regulators of transforming growth factor-beta (TGFB) and latent TGFB-binding proteins (LTBP)1 and 2. In the second, less conservative method, all transcripts with P < 0.01 and changed in the same direction in both datasets were considered. This yielded an additional 20 transcripts that were not identified in the first analysis, for a total of 42 common transcripts. These transcripts were regulators of functions such as inflammatory balance and matrix remodeling. In the third method, transcripts with Q < 0.10 were subject to pathway analysis, and common pathways were identified. Retinoic acid signaling and classical interferon signaling pathways were identified with this method. Finally, regulation by interferon tau (IFNT) was investigated. Among the 42 transcripts identified, 32 were regulated by IFNT in cultured luteal cells (Q < 0.05). Among those not regulated by IFNT were LTBP1 and 2, which are TGFB-binding proteins. In summary, common transcripts from two studies of the luteal transcriptome during early pregnancy were combined and shared changes were identified. This not only generated a list of potential key luteal regulators, which were mostly IFNT regulated, but also included transcripts not regulated by IFNT, including LTBP1 and 2. Two studies of the transcriptome of the bovine corpus luteum (CL) during early pregnancy were combined to identify the key regulators of luteal rescue. Among the genes that were revealed as potentially important regulators of the CL in early pregnancy were interferon-stimulated genes, regulators of transforming growth factor-beta and the retinoic acid pathway, a matrix metallopeptidase inhibitor, and regulators of immune function, including a chemokine.

Automated summary

This study combined two independent studies of global changes in the corpus luteum during early pregnancy to identify key regulators of luteal rescue, revealing 42 common transcripts that regulate functions such as inflammatory balance and matrix remodeling. Important regulators identified include interferon-stimulated genes, regulators of transforming growth factor-beta, and retinoic acid signaling pathways.