Athanasouli, ParaskeviBalli, MartinaDe Jaime-Soguero, AnchelBoel, AnnekatrienPapanikolaou, Sofiavan der Veer, Bernard K.Janiszewski, AdrianVanhessche, TijsFrancis, AnnickEl Laithy, YoussefLo Nigro, AntonioAulicino, Francesco, 1987-Koh, Kian PengPasque, VincentCosma, Maria Pia, 1970-Verfaillie, CatherineZwijsen, AnHeindryckx, BjörnNikolaou, ChristoforosLluis Vinas, Frederic2023-06-122023-06-122023Athanasouli P, Balli M, De Jaime-Soguero A, Boel A, Papanikolaou S, van der Veer BK, Janiszewski A, Vanhessche T, Francis A, El Laithy Y, Nigro AL, Aulicino F, Koh KP, Pasque V, Cosma MP, Verfaillie C, Zwijsen A, Heindryckx B, Nikolaou C, Lluis F. The Wnt/TCF7L1 transcriptional repressor axis drives primitive endoderm formation by antagonizing naive and formative pluripotency. Nat Commun. 2023 Mar 3;14:1210. DOI: 10.1038/s41467-023-36914-12041-1723http://hdl.handle.net/10230/57144Supplemental material files: supplementary information: online appendix; replication fileEarly 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.application/pdfeng© The Author(s) 2023. 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.EmbrionsEmbriologiaCèl·lules mareinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-023-36914-1info:eu-repo/semantics/openAccess