VGLL1 contributes to both the transcriptome and epigenome of the developing trophoblast compartment

The trophectoderm (TE), the first lineage specified during mammalian development, initiates implantation and gives rise to placental trophoblasts. While animal models have elucidated key conserved signaling pathways involved in early TE specification, including bone morphogenetic protein (BMP), WNT, and HIPPO, species-specific differences during early development emphasize the need for human-specific models. We previously identified VGLL1, a coactivator of TEAD transcription factors, as a human-specific placental marker. In this study, we employed a pluripotent stem cell (PSC)-based model of TE induction by BMP4 to investigate chromatin remodeling and transcriptional dynamics during TE formation. BMP4-induced chromatin accessibility changes promoted a trophoblast gene expression program, while mesoderm lineage markers were only transiently expressed upon canonical WNT activation. We found that VGLL1 was expressed downstream of key TE transcription factors (GATA2/3, TFAP2A/C) but was essential for establishment of full trophoblast identity by up-regulating the epidermal growth factor receptor (EGFR) and reinforcing GATA3 expression through positive feedback. Notably, VGLL1 enhanced canonical WNT signaling via direct regulation of WNT receptors and effectors. We also identified KDM6B, a histone demethylase that removes H3K27me3 repressive marks, as a direct VGLL1 target. KDM6B facilitated activation of bivalent promoters associated with TE markers, linking epigenetic regulation to lineage identity. Our findings establish a mechanistic framework positioning VGLL1 as a central regulator that integrates HIPPO, BMP, and WNT signaling pathways to drive establishment of human TE.

Authors

Institutions

Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-11-24
DOI
https://doi.org/10.1073/pnas.2508432122
Primary Topic
Pregnancy and preeclampsia studies
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

VGLL1 contributes to both the transcriptome and epigenome of the developing trophoblast compartment

Nirvay Sah, Jennifer N. Chousal, Sampada Kallol, Ahmed Abdelbaki et al.
Proceedings of the National Academy of Sciences
Pregnancy and preeclampsia studies
article

VGLL1 contributes to both the transcriptome and epigenome of the developing trophoblast compartment

Nirvay Sah, Jennifer N. Chousal, Sampada Kallol, Ahmed Abdelbaki, Pratik Home, Soumen Paul, Tony Bui, Heidi Cook‐Andersen, Ruben I. Calderon, Robert Morey, Claudia Gerri, Ryan Kittle, Kathleen M. Fisch, Francesca Soncin, Molly Huang, Peter De Hoff, Kathy K. Niakan, Norah M. E. Fogarty, Zoe Manalo, Chenguang Zheng, Walee B. Shaik
article en

Abstract

The trophectoderm (TE), the first lineage specified during mammalian development, initiates implantation and gives rise to placental trophoblasts. While animal models have elucidated key conserved signaling pathways involved in early TE specification, including bone morphogenetic protein (BMP), WNT, and HIPPO, species-specific differences during early development emphasize the need for human-specific models. We previously identified VGLL1, a coactivator of TEAD transcription factors, as a human-specific placental marker. In this study, we employed a pluripotent stem cell (PSC)-based model of TE induction by BMP4 to investigate chromatin remodeling and transcriptional dynamics during TE formation. BMP4-induced chromatin accessibility changes promoted a trophoblast gene expression program, while mesoderm lineage markers were only transiently expressed upon canonical WNT activation. We found that VGLL1 was expressed downstream of key TE transcription factors (GATA2/3, TFAP2A/C) but was essential for establishment of full trophoblast identity by up-regulating the epidermal growth factor receptor (EGFR) and reinforcing GATA3 expression through positive feedback. Notably, VGLL1 enhanced canonical WNT signaling via direct regulation of WNT receptors and effectors. We also identified KDM6B, a histone demethylase that removes H3K27me3 repressive marks, as a direct VGLL1 target. KDM6B facilitated activation of bivalent promoters associated with TE markers, linking epigenetic regulation to lineage identity. Our findings establish a mechanistic framework positioning VGLL1 as a central regulator that integrates HIPPO, BMP, and WNT signaling pathways to drive establishment of human TE.

Proceedings of the National Academy of SciencesVol. 122(48)
University of San Diego (US), Zagazig University (EG), The Francis Crick Institute (GB), University of California San Diego (US), University of Kansas Medical Center (US), Institut de Médecine de la Reproduction (FR)
California Institute for Regenerative Medicine, Wellcome Trust, Francis Crick Institute, Zagazig University, National Institutes of Health, Directorate for Biological Sciences, University of California, San Diego, Medical Research Council, Faculty of Science, Zagazig University, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Openalex Percentile: Top 54%
Pregnancy and preeclampsia studies
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.