Elucidation of the upstream transcription factors controlling preeclampsia-specific gene expression using human trophoblast stem cells as a model system

PROJECT SUMMARY Preeclampsia (PE) is a relatively common pregnancy disorder that originates from the placenta. It affects up to 8% of all human pregnancies and causes various maternal and fetal health problems, including maternal vascular dysfunction, proteinuria, and hypertension as well as growth restriction and preterm birth of the baby. It has no cure other than the delivery of the baby and can lead to eclampsia, which may result in death via stroke. It is generally accepted that defects in trophoblast lineage development, critical for proper implantation and placentation, are the leading cause of PE. However, the underlying molecular mechanisms of PE have not been well understood. While many genes upregulated or downregulated in PE have been identified by global gene expression analysis, upstream key transcription factors (TFs) responsible for the PE-specific gene expression programs (PE-driver TFs) and their action mechanisms have not yet been described. Furthermore, how such PE-driver TFs disrupt normal trophoblast lineage- specific gene regulatory networks remains unknown. The objectives of the proposed studies are to identify transcriptional and epigenetic regulators modulating PE-specific gene expression programs and to understand their action mechanisms by utilizing recently established human trophoblast stem cells (TSC) and their in vitro differentiation into syncytiotrophoblast (ST) and extravillous trophoblast (EVT) as a model system. Our preliminary studies suggested that the untimely or sustained upregulation of sequence- specific TFs may trigger abnormal expression of target genes known to be PE-specific, which may lead to impaired ST/EVT differentiation and, ultimately, PE phenotypes. To understand the molecular basis of PE, we will 1) identify and functionally validate putative PE-driver TFs which can induce PE-specific gene expression programs by utilizing human TSC differentiation as a model and 2) understand the regulatory mechanisms PE-driver TFs by mapping their downstream target genes and interaction partner proteins. The successful completion of this proposal will provide us with new models for studying the pathophysiology of human PE, illumination of molecular regulatory mechanisms underlying PE, and thus enhance our ability to generate novel diagnostic tools and therapeutics to improve healthcare for both the women with PE and their babies in the near future.