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PreprintCited by 1Hippo pathway signaling and YAP/TAZDevelopmental Biology and Gene RegulationPluripotent Stem Cells Research

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YAP1 and QSER1 are Key Modulators of Embryonic Signaling Pathways in the Mammalian Epiblast

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Abraham, Elizabeth, Roule, Thomas, Douglas, Aidan, Megill, Emily, Pericak, Olivia M., Howe, Jordan E., Choya-Foces, Carmen, Garbincius, Joanne F., Cohen, Henry M., Roig-Flórez, Paula, Zubillaga, Mikel, Andrake, Mark D., Kim, Seonhee, Elrod, John W., Akizu, Naiara, Estaras, Conchi·2025·EMBO Reports
DOI 10.1101/2025.06.16.659935PMC PMC13172546

Preprint — published as 10.1038/s44319-026-00746-z · Paper page

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Abstract

YAP1 signaling is essential for development but its specific roles in early embryogenesis remain poorly understood. To shed light on this, we analyzed YAP1’s role in regulating the pluripotency of the mammalian epiblast, using scRNAseq approaches. Conditional deletion of Yap1 in the mouse epiblast ( Sox2 -Cre) altered the expression of signaling genes, including Nodal , Wnt3 , and Fgf8 . Accordingly, Yap1 loss led to enhanced differentiation of the epiblast toward primitive streak lineages, as evidenced by the upregulation of T/ Brachyury and Eomes genes. Furthermore, a proximity labeling assay in human pluripotent stem cells, followed by biochemical assays and molecular modeling predictions, revealed that YAP1 cooperates with QSER1 protein to regulate lineage genes. Our analysis shows that YAP1:TEAD4 enhancers recruit QSER1 to prevent RNA Polymerase II recruitment. Accordingly, QSER1 depletion, similar to YAP1, increases NODAL gene expression and leads to hyperactive NODAL signaling in human 2D-gastruloids. Overall, our findings define a role of YAP1 in the epiblast in vivo and uncovered an interplay with QSER1 controlling the activity of developmental signaling pathways in pluripotent cells.

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Metadata

Authors
Abraham, E., Roule, T., Douglas, A., Megill, E., Pericak, O. M., Howe, J. E., Choya-Foces, C., Garbincius, J. F., Cohen, H. M., Roig-Flórez, P., Zubillaga, M., Andrake, M. D., Kim, S., Elrod, J. W., Akizu, N., & Estaras, C.
Affiliations
  • Temple University (US)
  • Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA
  • Fox Chase Cancer Center (US)
  • Children's Hospital of Philadelphia (US)
  • Department of Cardiovascular Sciences, Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
ORCID
Venue
EMBO Reports
Publisher
openRxiv
Published
2025-06-17
Volume
27
Issue
9
Pages
2369-2405
ISSN
1469-221X (ISSN-L)
DOI
10.1101/2025.06.16.659935
PMC
PMC13172546
OpenAlex
W7140604682
Cited by
1
References
1
Citations by year
2025: 1
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (CA030199, CA006927)
  • National Heart, Lung, and Blood Institute (T32HL091804)
  • National Cancer Institute (P30CA006927, P30CA030199)
  • National Institute of General Medical Sciences (T32GM142606)
  • National Institute of Neurological Disorders and Stroke (R01NS119699)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD106969, R01HD106969, F31HD113419)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Keywords
YAP, epiblast, pluripotency, Nodal signaling, Wnt3, FGF8, Brachyury, Eomes, RNA polymerase II recruitment, human pluripotent stem cells, early embryonic development

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