Downregulated luteolytic pathways in the transcriptome of early pregnancy bovine corpus luteum are mimicked by interferon-tau in vitro

Raghavendra Basavaraja,Gilgi Friedlander,Sai Kumar,Lonice Bibi,Jessica N Drum,Jackson Sapuleni,Rina Meidan,Roberto Sartori

doi:10.1186/s12864-021-07747-3

Raghavendra Basavaraja, Gilgi Friedlander + Show 6 more

Open Access

https://doi.org/10.1186/s12864-021-07747-3

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Abstract

BackgroundMaintenance of the corpus luteum (CL) beyond the time of luteolysis is essential for establishing pregnancy. Identifying the distinct features of early pregnancy CL remains unresolved, hence we analyzed here the transcriptome of CL on day 18 pregnant (P) and non-pregnant (NP) cows using RNA-Seq. CL of P cows expressed ISGs, verifying exposure to the pregnancy recognition signal, interferon-tau (IFNT), whereas the CL of NP cows had elevated luteal progesterone levels, implying that luteolysis had not yet commenced.ResultsThe DEGs, IPA, and metascape canonical pathways, along with GSEA analysis, differed markedly in the CL of P cows from those of NP cows, at the same day of the cycle. Both metascape and IPA identified similar significantly enriched pathways such as interferon alpha/beta, sonic hedgehog pathway, TNFA, EDN1, TGFB1, and PDGF. However, type-1 interferon and sonic hedgehog pathways were positively enriched whereas most of the enriched pathways were downregulated in the P compared to NP samples. Thirty-four % of these pathways are known to be elevated by PGF2A during luteolysis. Notably, selective DEGs in luteinized granulosa cells were modulated by IFNT in vitro in a similar manner to their regulation in the CL of P cows.ConclusionThis study unraveled the unique transcriptomic signature of the IFNT-exposed, early pregnancy CL, highlighting the abundance of downregulated pathways known to be otherwise induced during luteolysis. These and IFNT-regulated in vitro pregnancy-specific DEGs suggest that IFNT contributes to the characteristics and maintenance of early pregnancy CL.

Highlights

Maintenance of the corpus luteum (CL) beyond the time of luteolysis is essential for establishing pregnancy
Principal component analysis (PCA) was used to assess the overall mRNA profile differences among the samples; it showed that the P and NP samples were clustered separately (Supplementary Figure 1)
Several findings here indicate that the CL of P cows were exposed to IFNT, including the enrichment of the interferon alpha (IFNA)/B signaling pathway, IFN and its receptors were identified as an upstream regulators along with various Interferonstimulated genes (ISGs) differentially expressed in the P compared to NP analysis

Summary

Introduction

Maintenance of the corpus luteum (CL) beyond the time of luteolysis is essential for establishing pregnancy. All of them act through the classical type-1 interferon pathway and stimulate the Interferonstimulated genes (ISGs) in the endometrium [10,11,12,13]. These ISGs include the interferon regulatory factors (IRFs) family, ISG15, MX1 (MX Dynamin Like GTPase 1), MX2, 2′-5′-Oligoadenylate Synthetase 1 (OAS1Y), and signal transducer and activator of transcription (STATs) [14,15,16,17,18]. There is ample evidence that IFNT acts in the endometrium to inhibit uterine pulses of PGF2A [8, 9, 21, 22] during maternal recognition of pregnancy. Our in vitro data, which show the effects of IFNT on luteal cells [16, 17, 27], further support a direct role of IFNT on luteal function

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