Abstract
Assisted reproduction technologies (ARTs) are becoming increasingly common. Therefore, how these procedures influence gene regulation and foeto-placental development are important to explore. Here, we assess the effects of blastocyst transfer on mouse placental growth and transcriptome. C57Bl/6 blastocysts were transferred into uteri of B6D2F1 pseudopregnant females and dissected at embryonic day 10.5 for analysis. Compared to non-transferred controls, placentas from transferred conceptuses weighed less even though the embryos were larger on average. This suggested a compensatory increase in placental efficiency. RNA sequencing of whole male placentas revealed 543 differentially expressed genes (DEGs) after blastocyst transfer: 188 and 355 genes were downregulated and upregulated, respectively. DEGs were independently validated in male and female placentas. Bioinformatic analyses revealed that DEGs represented expression in all major placental cell types and included genes that are critical for placenta development and/or function. Furthermore, the direction of transcriptional change in response to blastocyst transfer implied an adaptive response to improve placental function to maintain foetal growth. Our analysis revealed that CpG methylation at regulatory regions of two DEGs was unchanged in female transferred placentas and that DEGs had fewer gene-associated CpG islands (within ~20 kb region) compared to the larger genome. These data suggested that altered methylation at proximal promoter regions might not lead to transcriptional disruption in transferred placentas. Genomic clustering of some DEGs warrants further investigation of long-range, cis-acting epigenetic mechanisms including histone modifications together with DNA methylation. We conclude that embryo transfer, a protocol required for ART, significantly impacts the placental transcriptome and growth.
Highlights
More than seven million babies worldwide have been born using some form of assisted reproduction technology (ART) largely as a treatment approach to infertility (European Society of Human Reproduction and Embryology (ESHRE) 2018 February 18
Since optimal placental function is required for normal foetal growth and development, it is predicted that placenta pathologies are responsible for some of the adverse pregnancy outcomes associated with ART (Delle Piane et al 2010, Thomopoulos et al 2013, Choux et al 2015)
Downregulated differentially expressed genes (DEGs) were less frequently associated with proximal promoter CpG islands (26% of DEGs, P = 0.025) than both upregulated DEGs and the genome (42% of genes; Fig. 4A). These findings suggested that genes that were differentially expressed after blastocyst transfer were less likely to be cis-regulated by intragenic or proximal promoter CpG methylation compared to the genome at large
Summary
More than seven million babies worldwide have been born using some form of assisted reproduction technology (ART) largely as a treatment approach to infertility (European Society of Human Reproduction and Embryology (ESHRE) 2018 February 18. While ART is generally safe, growing evidence suggests that individuals born using these technologies are at an increased risk of intrauterine growth restriction, perinatal complications (Quinn & Fujimoto 2016), and/ or developing cardiovascular disease later in life (Tararbit et al 2013, Valenzuela-Alcaraz et al 2013, Liu et al 2015, Guo et al 2017). Since optimal placental function is required for normal foetal growth and development, it is predicted that placenta pathologies are responsible for some of the adverse pregnancy outcomes associated with ART (Delle Piane et al 2010, Thomopoulos et al 2013, Choux et al 2015). ART pregnancies were overrepresented in the highest quartile of placental weight and underrepresented in the highest quartile of birthweight (Haavaldsen et al 2012)
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