Institute for Reproductive and Developmental Sciences, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA.
Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
Nat Commun. 2023 Aug 10;14(1):4826. doi: 10.1038/s41467-023-40424-5.
The extravillous trophoblast cell lineage is a key feature of placentation and successful pregnancy. Knowledge of transcriptional regulation driving extravillous trophoblast cell development is limited. Here, we map the transcriptome and epigenome landscape as well as chromatin interactions of human trophoblast stem cells and their transition into extravillous trophoblast cells. We show that integrating chromatin accessibility, long-range chromatin interactions, transcriptomic, and transcription factor binding motif enrichment enables identification of transcription factors and regulatory mechanisms critical for extravillous trophoblast cell development. We elucidate functional roles for TFAP2C, SNAI1, and EPAS1 in the regulation of extravillous trophoblast cell development. EPAS1 is identified as an upstream regulator of key extravillous trophoblast cell transcription factors, including ASCL2 and SNAI1 and together with its target genes, is linked to pregnancy loss and birth weight. Collectively, we reveal activation of a dynamic regulatory network and provide a framework for understanding extravillous trophoblast cell specification in trophoblast cell lineage development and human placentation.
滋养外胚层细胞谱系是胎盘形成和成功妊娠的一个关键特征。对于驱动滋养外胚层细胞发育的转录调控的了解是有限的。在这里，我们绘制了人类滋养层干细胞及其向滋养外胚层细胞转化的转录组和表观基因组图谱以及染色质相互作用。我们表明，整合染色质可及性、长程染色质相互作用、转录组和转录因子结合基序富集，可以鉴定出对滋养外胚层细胞发育至关重要的转录因子和调控机制。我们阐明了 TFAP2C、SNAI1 和 EPAS1 在调节滋养外胚层细胞发育中的功能作用。EPAS1 被确定为关键的滋养外胚层细胞转录因子（包括 ASCL2 和 SNAI1）的上游调节剂，其与靶基因一起与妊娠丢失和出生体重有关。总的来说，我们揭示了一个动态调控网络的激活，并为理解滋养外胚层细胞在滋养层细胞谱系发育和人类胎盘形成中的特化提供了一个框架。
