Global Epigenome and Transcriptome Maps of Human Trophoblast Cell Lineage Development [Placenta_ChIP]

The extravillous trophoblast (EVT) cell lineage is a key feature of placentation and critical for spiralartery remodeling and successful pregnancy. Our 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 the differentiated EVT cell lineage. We identified that chromatin accessibility in intergenic regions was more extensive in EVT cells than in TS cells in the stem state, which is indicative of increased enhancer-driven gene regulation. Using reference epigenome annotation, we noted that 18% of the chromatin landscape in EVT cells was uncharted. We linked regulatory regions to their cognate target genes and characterized the three-dimensional organization of the TS cell functional genome by Hi-C. Integrational analysis of chromatin accessibility, long-range chromatin interactions, transcriptomic, and transcription factor binding motif enrichment enabled identification of transcription factors and regulatory mechanisms associated with EVT cell lineage development. Subsequent analyses elucidated functional roles forTFAP2C,EPAS1,SNAI1, andDLX6in the regulation of EVT cell lineage development.EPAS1was identified as an upstream regulator of EVT cell transcription factors, includingSNAI1andDLX6, and was found to be upregulated in idiopathic recurrent pregnancy loss. 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. ChIP was performed on a hTSC line,TSCT-1 (CT27), established in our previous study (Okae et al. Cell Stem Cell 2018) using the ChIP Reagents (NIPPON GENE).