Dissecting the regulatory mechanisms driving trophoblast cell fate

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Interactions between the placenta and uterus are essential for reproductive success in humans, and defects in this communication underlie common pregnancy complications such as pre-eclampsia. During placentation, trophoblast cells of the placenta infiltrate the uterus, transforming the maternal arteries into high conductance vessels. This process is largely unexplored in humans due to poor accessibility of this tissue during early pregnancy and, until recently, a lack of faithful in vitro models. Our single-cell transcriptomic census of the first-trimester human placental-uterine interface (Nature 2018) described novel maternal and fetal cells, and potential interactions between them. Here, we will develop and use state-of-the-art genomics, computational, cellular and bioengineering tools to investigate how trophoblast cells differentiate, invade the uterus, and interact with maternal cells with a focus on cell-intrinsic mechanisms and environmental cues. In Aim 1, we will build a roadmap of the early human placental-uterine interface by mapping the uncharacterised spatial and open chromatin landscape of the placental cells and accurately reconstructing their gene regulatory programmes and cell-cell communication events. In Aim 2, we will validate the main transcription factors predicted to be involved in trophoblast identity by recording the in vitro differentiation trajectories of trophoblast organoids with lineage tracing and using gene-editing approaches to perturb them. Our experiments will be guided by a novel computational framework to compare in vivo and in vitro systems. In Aim 3, we will bioengineer advanced co-culture models of the placental-uterine interface. The development of these platforms will enable us to mechanistically dissect the influence of maternal uterine cells on trophoblast identity. Our proposal will reconstruct the early events of human placentation and provide fundamental knowledge on the regulation of cell identity during development.