Pregnancy-induced changes in the transcriptome of the bovine corpus luteum during and after embryonic interferon-tau secretion

Authors: MEZERA, MEGAN - University Of Wisconsin; Li, Wenli; MEIDAN, RINA - Hebrew University Of Jerusalem; WILTBANK, MILO - University Of Wisconsin

Submitted to: Biology of Reproduction
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/3/2021
Publication Date: 3/4/2021
Citation: Mezera, M., Li, W., Meidan, R., Wiltbank, M. 2021. Pregnancy-induced changes in the transcriptome of the bovine corpus luteum during and after embryonic interferon-tau secretion. Biology of Reproduction. 105(1):148-163. https://doi.org/10.1093/biolre/ioab034.
DOI: https://doi.org/10.1093/biolre/ioab034

Interpretive Summary: Luteal maintenance has been of interest for many decades as a vital component to reproductive success. Despite this, mechanisms underlying this process are not fully understood. Traditional studies used controls of differential corpus luteum (CL) ages. This study first used bi-hourly blood sampling to ensure nonpregnant control CL was of similar age. Then, we used whole transcriptome RNA sequencing to compare the gene expression profiles among CL tissues collected from control group, first- and second-month pregnancy. Of note, the present study has resulted in the novel finding that a substantial subset of interferon-stimulated genes (ISG), long known to be up-regulated in the first month, remain persistently elevated into second-month pregnancy. Yet, the mechanisms of maintenance between these two appear to be distinct, as reflected by differences in the CL transcriptome profile and circulating hormonal profiles. Our study provided evidence for potentially active and distinctive models of CL maintenance during first and second month of pregnancy, highlighting further investigation into the distinct molecular mechanisms required for maintaining pregnancy during the first and second months.

Technical Abstract: Understanding luteal maintenance during maternal recognition of pregnancy is important for understanding how mammalian pregnancy is maintained. However, characterizing effects of early pregnancy has historically been confounded by use of controls confounded by exposure to early prostaglandin (PGF) pulses or have differences in corpus luteum (CL) age. To avoid this, the present study utilized bihourly blood sampling to ensure nonpregnant control CL (n=6) were of a similar age to CL from pregnant animals (n=5), yet without exposure to PGF pulses. Additionally, CL from second month of pregnancy (n=4) were analyzed to track fate of altered genes after cessation of embryonic interferon tau (IFNT) secretion. The major alteration in gene expression in first month of pregnancy occurred in ISG, with immune/interferon signaling pathways enriched in three independent over-representation analyses. Surprisingly, a subset of these did not return to control concentrations in the second month with cessation of IFNT secretion. Investigation of luteolytic genes found few altered transcripts, in contrast to previous reports, likely due to removal of controls exposed to PGF pulses. An exception to this trend was decreased expression of transcription factor NR4A1. Beyond luteolytic genes and ISGs, over representation analyses highlighted the prevalence of altered genes within the extracellular matrix and regulation of insulin-like growth factor availability, confirming results of other studies independent of luteolytic genes. Most of these results support the idea that maintenance of the CL in early pregnancy is due to lack of PGF exposure rather than an active anti-luteolytic mechanism.