The Wnt/TCF7L1 transcriptional repressor axis drives primitive endoderm formation by antagonizing naive and formative pluripotency

Paraskevi Athanasouli, Martina Balli, Anchel Jaime-Soguero (), Annekatrien Boel, Sofia Papanikolaou, Bernard K. Veer, Adrian Janiszewski, Tijs Vanhessche, Annick Francis, Youssef El Laithy, Antonio Lo Nigro, Francesco Aulicino, Kian Peng Koh, Vincent Pasque, Maria Pia Cosma, Catherine Verfaillie, An Zwijsen, Björn Heindryckx, Christoforos Nikolaou and Frederic Lluis ()
Additional contact information
Paraskevi Athanasouli: KU Leuven, Department of Development and Regeneration, Stem Cell Institute
Martina Balli: KU Leuven, Department of Development and Regeneration, Stem Cell Institute
Anchel Jaime-Soguero: KU Leuven, Department of Development and Regeneration, Stem Cell Institute
Annekatrien Boel: Ghent University Hospital
Sofia Papanikolaou: University of Crete
Bernard K. Veer: KU Leuven, Department of Development and Regeneration, Stem Cell Institute
Adrian Janiszewski: KU Leuven, Department of Development and Regeneration, Stem Cell Institute
Tijs Vanhessche: KU Leuven, Department of Development and Regeneration, Stem Cell Institute
Annick Francis: Department of Cardiovascular Sciences, KU Leuven
Youssef El Laithy: KU Leuven, Department of Development and Regeneration, Stem Cell Institute
Antonio Lo Nigro: KU Leuven, Department of Development and Regeneration, Stem Cell Institute
Francesco Aulicino: Centre for Genomic Regulation (CRG), Dr Aiguader 88
Kian Peng Koh: KU Leuven, Department of Development and Regeneration, Stem Cell Institute
Vincent Pasque: KU Leuven, Department of Development and Regeneration, Stem Cell Institute
Maria Pia Cosma: Centre for Genomic Regulation (CRG), Dr Aiguader 88
Catherine Verfaillie: KU Leuven, Department of Development and Regeneration, Stem Cell Institute
An Zwijsen: Department of Cardiovascular Sciences, KU Leuven
Björn Heindryckx: Ghent University Hospital
Christoforos Nikolaou: Computational Genomics Group, Institute of Bioinnovation, Biomedical Sciences Research Center “Alexander Fleming”
Frederic Lluis: KU Leuven, Department of Development and Regeneration, Stem Cell Institute

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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, TCF7L1 is required for PE specification as deletion of Tcf7l1 abrogates PE differentiation without restraining epiblast priming. Taken together, our study underscores the importance of transcriptional Wnt inhibition in regulating lineage specification in ESCs and preimplantation embryo development as well as identifies TCF7L1 as key regulator of this process.

Date: 2023
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DOI: 10.1038/s41467-023-36914-1

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