Transcriptomic Drivers of Differentiation, Maturation, and Polyploidy in Human Extravillous Trophoblast.

Robert Morey,Mana M Parast,Louise C Laurent,Omar Farah,Morgan Meads,Sampada Kallol,Francesca Soncin,Matteo Moretto-Zita,Daniela F Requena

doi:10.3389/fcell.2021.702046

Abstract

During pregnancy, conceptus-derived extravillous trophoblast (EVT) invades the endomyometrium, anchors the placenta to the maternal uterus, and remodels the spiral arteries in order to establish maternal blood supply to the fetoplacental unit. Recent reports have described early gestation EVT as polyploid and senescent. Here, we extend these reports by performing comprehensive profiling of both the genomic organization and transcriptome of first trimester and term EVT. We define pathways and gene regulatory networks involved in both initial differentiation and maturation of this important trophoblast lineage at the maternal–fetal interface. Our results suggest that like first trimester EVT, term EVT undergoes senescence and endoreduplication, is primarily tetraploid, and lacks high rates of copy number variations. Additionally, we have highlighted senescence and polyploidy-related genes, pathways, networks, and transcription factors that appeared to be important in normal EVT differentiation and maturation and validated a key role for the unfolded protein response in this context.

Highlights

The human placenta is essential for successful pregnancy and unique in its transitory nature
Our results suggest that term extravillous trophoblast (EVT) lack high rates of copy number variation (CNV), though studies using WGS with substantially larger sample sizes are needed to definitively identify or rule-out the presence of functionally relevant under- or over-represented genomic regions
We have highlighted senescence and polyploidy-related genes, pathways, networks, and TFs that appeared to be important in extravillous trophoblast (EVT) differentiation and maturation and have validated a critical role for the UPR in formation of functional EVT

Summary

Introduction

The human placenta is essential for successful pregnancy and unique in its transitory nature. It performs a multitude of functions, including gas and nutrient exchange, synthesis of pregnancyspecific signaling molecules, and induction of maternal immunological tolerance. One such study in the human placenta showed an enrichment of CNVs, suggesting that, as in the mouse, the human placenta contains an atypical genome architecture that is important for the normal function of the organ (Kasak et al, 2015). Another study focused on invasive EVT in first trimester human placenta and reported that, unlike mouse TGCs, these cells did not contain CNVs but were predominantly tetraploid, and potentially undergo senescence and endoreduplication (Velicky et al, 2018). To date, similar analysis of term EVT has not been done

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