Active remodeling of the chromatin landscape directs extravillous trophoblast cell lineage development

The extravillous trophoblast (EVT) cell lineage is a key feature of placentation and successful pregnancy. Knowledge of transcriptional regulation driving EVT cell development is limited. Here, we mapped the transcriptome and epigenome landscape as well as chromatin interactions of human trophoblast stem (TS) cells and their transition into EVT cells. Integration of chromatin accessibility, long-range chromatin interactions, transcriptomic, and transcription factor (TF) binding motif enrichment enabled identification of TFs and regulatory mechanisms associated with EVT cell development. Functional roles for TFAP2C, SNAI1, and EPAS1 in the regulation of EVT cell development were elucidated. EPAS1 was identified as an upstream regulator of key EVT cell TFs, including ASCL2 and SNAI1 and together with its target genes, was linked to pregnancy loss and birth weight. Collectively, we have revealed activation of a dynamic regulatory network that provides a framework for understanding EVT cell specification in trophoblast cell lineage development and human placentation.