Human placentation defects are commonly associated with adverse pregnancy outcomes, such as preeclampsia and intrauterine growth restrictions. Despite its clinical relevance, the molecular pathways controlling placental development are poorly understood. Emerging evidence from mouse models with intrinsic genomic instability suggests that fundamental cellular processes, such as DNA replication, are essential for the proper development of the placenta. However, the exact molecular mechanism is unknown, and it's not clear whether maintenance of genomic integrity is also essential for human placental development. This proposal aims to identify novel regulators of placental development by knocking down the expression of genes involved in genome maintenance, such as DNA replication, DNA damage response, and repair, in mouse and human trophoblast stem cells using CRISPR-based transcriptional interference coupled with single-nuclei transcriptomics. Successful completion of this project will further our understandings of the regulation of genomic stability in placental cells and provide novel insights into how defects in genome maintenance affect human pregnancy outcomes which are currently underexplored.