Around one in five pregnancies ends in complications like pre-eclampsia, stillbirth, or preterm birth, yet doctors cannot reliably predict which pregnancies are at risk. The culprit may lie in ancient viral DNA stitched into the human genome—endogenous retroviruses (ERVs)—which help control how the placenta invades the womb. This project will map genetic and epigenetic variations in ERVs from placental tissue, then test those variants using lab-grown placental organoids to see how they disrupt development. If successful, the work could produce a set of molecular markers that flag placental insufficiency early, allowing clinicians to screen for at-risk pregnancies before complications arise. It would also reveal how ERVs regulate genes in the placenta’s unique chromatin environment—fundamental biology that may explain why the placenta is so prone to failure. While the immediate payoff is diagnostic, the mechanistic insights could eventually point toward therapies that restore normal placental function, reducing maternal and fetal harm worldwide.
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Complications of pregnancy, such as pre-eclampsia, fetal growth restriction, stillbirth and spontaneous preterm birth, affect ~20 % of human pregnancies, causing maternal and fetal morbidity and mortality. Although the molecular aetiology of these disorders is not well understood, they are thought to share a common pathogenesis in insufficient uterine invasion by the placenta. An understudied component of the human genome, known as endogenous retroviruses (ERVs), contributes hundreds of gene-regulatory sequences key for human placental physiology. However, assessment of genetic and epigenetic variation at ERVs in human disease is currently missing. Here, I will delineate the role of ERVs in placentally-derived pregnancy complications. Guided by my previous identification of functional ERV families in human placenta, I will detect genetic and epigenetic ERV variants in placenta. Then, I will use human trophoblast organoids (hTO), to test genetic and epigenetic variation functionally, and elucidate associated signalling pathways. This project will delineate the role of ERVs in placental development and pregnancy complications, revealing markers of placental insufficiency, allowing screening of at-risk pregnancies. Further, my proposed experiments will provide mechanistic insights into the role of ERVs in genome regulation, particularly in the unique placental chromatin environment, opening avenues for future research, and therapeutic targets.
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