Extravillous trophoblast cell lineage development is associated with active remodeling of the chromatin landscape

Kaela M. Varberg (), Esteban M. Dominguez, Boryana Koseva, Joseph M. Varberg, Ross P. McNally, Ayelen Moreno-Irusta, Emily R. Wesley, Khursheed Iqbal, Warren A. Cheung, Carl Schwendinger-Schreck, Craig Smail, Hiroaki Okae, Takahiro Arima, Michael Lydic, Kristin Holoch, Courtney Marsh, Michael J. Soares () and Elin Grundberg ()
Additional contact information
Kaela M. Varberg: University of Kansas Medical Center
Esteban M. Dominguez: University of Kansas Medical Center
Boryana Koseva: Children’s Mercy Kansas City
Joseph M. Varberg: Stowers Institute for Medical Research
Ross P. McNally: University of Kansas Medical Center
Ayelen Moreno-Irusta: University of Kansas Medical Center
Emily R. Wesley: Children’s Mercy Kansas City
Khursheed Iqbal: University of Kansas Medical Center
Warren A. Cheung: Children’s Mercy Kansas City
Carl Schwendinger-Schreck: Children’s Mercy Kansas City
Craig Smail: Children’s Mercy Kansas City
Hiroaki Okae: Tohoku University Graduate School of Medicine
Takahiro Arima: Tohoku University Graduate School of Medicine
Michael Lydic: University of Kansas Medical Center
Kristin Holoch: University of Kansas Medical Center
Courtney Marsh: University of Kansas Medical Center
Michael J. Soares: University of Kansas Medical Center
Elin Grundberg: University of Kansas Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40424-5

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