The Wnt/TCF7L1 transcriptional repressor axis drives primitive endoderm formation by antagonizing naive and formative pluripotency
Open accessPreprint — published as 10.1038/s41467-023-36914-1 · Paper page
Abstract
Early during preimplantation development and in heterogeneous mouse embryonic stem cells (mESC) culture, pluripotent cells are specified towards either the primed epiblast or the primitive endoderm (PE) lineage. Canonical Wnt signaling is crucial for safeguarding naive pluripotency and embryo implantation, yet the role and relevance of canonical Wnt inhibition during early mammalian development remains unknown. Here, we demonstrate that transcriptional repression exerted by Wnt/TCF7L1 promotes PE differentiation of mESCs and in preimplantation inner cell mass. Time-series RNA sequencing and promoter occupancy data reveal that TCF7L1 binds and represses genes encoding essential naive pluripotency factors and indispensable regulators of the formative pluripotency program, including Otx2 and Lef1 . Consequently, TCF7L1 promotes pluripotency exit and suppresses epiblast lineage formation, thereby driving cells into PE specification. Conversely, deletion of Tcf7l1 abrogates PE differentiation without restraining epiblast priming. Taken together, our study underscores the importance of transcriptional Wnt inhibition in regulating lineage segregation in ESCs and preimplantation embryo development as well as identifies TCF7L1 as key regulator of this process.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Tcf7l1 and Tbx3 are well-known repressors in development, but had not been directly linked to hepatocyte zonation.
“Tcf7l1 and Tbx3 are indeed well-known repressors in development68,69, but had not been directly linked to hepatocyte zonation.”
From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [68]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
No references could be resolved yet.
Research works printed but not linked: 17
- Hermitte, S. & Chazaud, C. Primitive endoderm differentiation: from specification to epithelium formation. Philos. Trans. R. Soc. B Biol. Sci. 369, 20130537 (2014).
- Fan, R. et al. Wnt/Beta-catenin/Esrrb signalling controls the tissue-scale reorganization and maintenance of the pluripotent lineage during murine embryonic diapause. Nat. Commun. 11, 5499 (2020).
- Xu, Z. et al. Wnt/β-catenin signaling promotes self-renewal and inhibits the primed state transition in naïve human embryonic stem cells. Proc. Natl. Acad. Sci. U. S. A. 113, E6382-E6390 (2016).
- De Jaime-Soguero, A. et al. Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus. PLOS Genet. 13, e1006682 (2017).
- Liang, R. & Liu, Y. Tcf7l1 directly regulates cardiomyocyte differentiation in embryonic stem cells. Stem Cell Res. Ther. 9, 267 (2018).
- Morris, S. A. et al. Origin and formation of the first two distinct cell types of the inner cell mass in the mouse embryo. Proc. Natl. Acad. Sci. U. S. A. 107, 6364-6369 (2010).
- de Jaime-Soguero, A., Abreu de Oliveira, W. A. & Lluis, F. The Pleiotropic Effects of the Canonical Wnt Pathway. Genes (Basel). 9, 93 (2018).
- Mohamed, O. A. et al. Uterine Wnt/β-catenin signaling is required for implantation. Proc. Natl. Acad. Sci.
- Lluis, F. et al. T-cell factor 3 (Tcf3) deletion increases somatic cell reprogramming by inducing epigenome modifications. Proc. Natl. Acad. Sci. U. S. A. 108, 11912-7 (2011).
- Semrau, S. et al. Dynamics of lineage commitment revealed by single-cell transcriptomics of differentiating embryonic stem cells. Nat. Commun. 8, 1096 (2017).
- Brown, K. et al. A Comparative Analysis of Extra-Embryonic Endoderm Cell Lines. PLoS One 5, e12016 (2010).
- Morgani, S. M. & Brickman, J. M. LIF supports primitive endoderm expansion during pre-implantation development. 3488-3499 (2015) doi:10.1242/dev.125021. · DOI
- Zhou, Y. et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 10, 1523 (2019).
- Cole, M. F., Johnstone, S. E., Newman, J. J., Kagey, M. H. & Young, R. A. Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. Genes Dev. 746-755 (2008) doi:10.1101/gad.1642408.4. · DOI
- Merrill, B. J. et al. Tcf3 : a transcriptional regulator of axis induction in the early embryo. (2004) doi:10.1242/dev.00935. · DOI
- Moreira, S. et al. TCF7L1 and TCF7 differentially regulate specific mouse ES cell genes in response to GSK-3 inhibition. http://10.0.4.77/473801 (2018) doi:10.1101/473801. 108 · DOI
- Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014). 111
Cited by
Sorted by citations
Enhancer grammar of liver cell types and hepatocyte zonation states
González-Blas, C. B., Matetovici, I., Hillen, H., Taskiran, I. I., Vandepoel, R., Christiaens, V., Sansores-García, L., Verboven, E., Hulselmans, G., Poovathingal, S., et al. (2022) · doi:10.1101/2022.12.08.519575 · Cited by 5 · see citing works
- Authors
- Athanasouli, P., Balli, M., De Jaime-Soguero, A., Boel, A., Papanikolaou, S., van der Veer, B. K., Janiszewski, A., Francis, A., El Laithy, Y., Lo Nigro, A., Aulicino, F., Koh, K. P., Pasque, V., Cosma, M. P., Verfaille, C., Zwijsen, A., Heindryckx, B., Nikolaou, C., & Lluis, F.
- Affiliations
- Leuven Stem Cell Institute (BE)
- Ghent University Hospital (BE)
- University of Crete (GR)
- KU Leuven (BE)
- Centre for Genomic Regulation (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Alexander Fleming Biomedical Sciences Research Center (GR)
- ORCID
- Venue
- Nature Communications
- Publisher
- openRxiv
- Published
- 2022-05-19
- Volume
- 14
- Issue
- 1
- Pages
- 1210-1210
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9984534
- OpenAlex
- W4323046045
- Cited by
- 31
- References
- 0
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 8 · 2023: 3 · 2022: 2
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
- Lirias (KU Leuven) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fonds Wetenschappelijk Onderzoek (G092518N, 11M7822N, G0C6820N, G097618N, G091521N, G0B4420N, G0I7822N, G0C9320N, G073622N, 11E7920N)
- KU Leuven (C14/21/119, PDM/18/212, C14/21/115, G097618N, G0I7822N)
- Ministerio de Ciencia e Innovación (PID2020)
- Vlaamse regering (C14/21/119, C14/21/115)
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- Universitaire Ziekenhuizen Leuven, KU Leuven (PDM/18/212, C14/21/115)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- Wnt signaling, TCF7L1, primitive endoderm, naive pluripotency, transcriptional repression, Otx2, LEF1, preimplantation embryo, inner cell mass, mouse embryonic stem cells, lineage specification, Wnt signaling inhibition
- MeSH terms
- Animals, Automobile Driving, Blastocyst, Cell Differentiation, Endoderm, Female, Germ Layers, Pregnancy, Mice, Transcription Factor 7-Like 1 Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
