Abstract
Pregnancy rates for in vitro produced (IVP) embryos are usually lower than for embryos produced in vivo after ovarian superovulation (MOET). This is potentially due to alterations in their trophectoderm (TE), the outermost layer in physical contact with the maternal endometrium. The main objective was to apply a multi-omics data integration approach to identify both temporally differentially expressed and differentially methylated genes (DEG and DMG), between IVP and MOET embryos, that could impact TE function. To start, four and five published transcriptomic and epigenomic datasets, respectively, were processed for data integration. Second, DEG from day 7 to days 13 and 16 and DMG from day 7 to day 17 were determined in the TE from IVP vs. MOET embryos. Third, genes that were both DE and DM were subjected to hierarchical clustering and functional enrichment analysis. Finally, findings were validated through a machine learning approach with two additional datasets from day 15 embryos. There were 1535 DEG and 6360 DMG, with 490 overlapped genes, whose expression profiles at days 13 and 16 resulted in three main clusters. Cluster 1 (188) and Cluster 2 (191) genes were down-regulated at day 13 or day 16, respectively, while Cluster 3 genes (111) were up-regulated at both days, in IVP embryos compared to MOET embryos. The top enriched terms were the KEGG pathway "focal adhesion" in Cluster 1 (FDR = 0.003), and the cellular component: "extracellular exosome" in Cluster 2 (FDR<0.0001), also enriched in Cluster 1 (FDR = 0.04). According to the machine learning approach, genes in Cluster 1 showed a similar expression pattern between IVP and less developed (short) MOET conceptuses; and between MOET and DKK1-treated (advanced) IVP conceptuses. In conclusion, these results suggest that early conceptuses derived from IVP embryos exhibit epigenomic and transcriptomic changes that later affect its elongation and focal adhesion, impairing post-transfer survival.
Highlights
Assisted reproductive technologies (ART) have been used in cattle breeding since the 1950s, generating millions of healthy animals since [1,2,3]
After artificial insemination (AI), the ART most frequently implemented in cattle reproduction is embryo transfer, where embryos are produced either (i) in vivo by ovarian superstimulation leading to multiple ovulations followed by AI, embryo collection and transfer (MOET) or (ii) in vitro embryo production (IVP), involving maturation and fertilization of oocytes collected from live animals via transvaginal aspiration of follicles or by recovery from the ovaries after slaughter
There were 6360 differentially methylated genes (DMG), corresponding to 4495 (70.7%) hypermethylated regions in the IVP group and 1865 regions (29.3%) in the MOET group
Summary
Assisted reproductive technologies (ART) have been used in cattle breeding since the 1950s, generating millions of healthy animals since [1,2,3]. One potential factor influencing embryo survival is impaired post-hatching elongation of IVP embryos, which begins at around day 13 of pregnancy [7]. Around this time, the trophectoderm (TE) begins to secrete interferon-tau, the pregnancy recognition factor in cattle [8]. Conceptuses derived from the transfer of IVP conceptuses were smaller at day 13 than their MOET counterparts [9], but were similar in length at day 16 and 17 [10, 11]. It has been demonstrated that the transcriptomic response of the endometrium differs between MOET- and IVP-derived conceptuses both in vivo [12, 13] and in vitro [14]
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