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

Creator(s)

Kaela M. Varberg
Esteban M. Dominguez
Boryana Koseva, Children's Mercy HospitalFollow
Joseph M. Varberg
Ross P. McNally
Ayelen Moreno-Irusta
Emily R. Wesley, Children's Mercy Kansas City
Khursheed Iqbal
Warren A. Cheung, Children's Mercy HospitalFollow
Carl F. Schreck, Children's Mercy Kansas CityFollow
Craig Smail, Children's Mercy Kansas CityFollow
Hiroaki Okae
Takahiro Arima
Michael Lydic
Kristin Holoch
Courtney Marsh
Michael J. Soares, Children's Mercy HospitalFollow
Elin Grundberg, Children's Mercy HospitalFollow

Document Type

Article

Publication Date

8-10-2023

Identifier

DOI: 10.1038/s41467-023-40424-5; PMCID: PMC10415281

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.

Journal Title

Nat Commun

Volume

14

Issue

1

First Page

4826

Last Page

4826

MeSH Keywords

Pregnancy; Female; Humans; Trophoblasts; Chromatin; Placentation; Cell Differentiation; Transcription Factors; Cell Lineage; Placenta; Basic Helix-Loop-Helix Transcription Factors

Keywords

Pregnancy; Trophoblasts; Chromatin; Placentation; Cell Differentiation; Transcription Factors; Cell Lineage; Placenta; Basic Helix-Loop-Helix Transcription Factors

Comments

Grant support

• F32HD096809/U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• K99HD107262/U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• GM146966/U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
• HG012422/U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)
• JP22gm1310001/Japan Agency for Medical Research and Development (AMED)

• HD020676/U.S. Department of Health & Human Services | National Institutes of Health (NIH)
• HD099638/U.S. Department of Health & Human Services | National Institutes of Health (NIH)
• HD105734/U.S. Department of Health & Human Services | National Institutes of Health (NIH)

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Publisher's Link: https://www.nature.com/articles/s41467-023-40424-5

Recommended Citation

Varberg KM, Dominguez EM, Koseva B, et al. Extravillous trophoblast cell lineage development is associated with active remodeling of the chromatin landscape. Nat Commun. 2023;14(1):4826. Published 2023 Aug 10. doi:10.1038/s41467-023-40424-5