The role of transposable elements in pregnancy complications (360G-Wellcome-301798_Z_23_Z)

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.