title: Inhibition of β-catenin-TCF1 interaction delays differentiation of mouse embryonic stem cells.
abstract: The ability of mouse embryonic stem cells (mESCs) to self-renew or differentiate into various cell lineages is regulated by signaling pathways and a core pluripotency transcriptional network (PTN) comprising Nanog, Oct4, and Sox2. The Wnt/β-catenin pathway promotes pluripotency by alleviating T cell factor TCF3-mediated repression of the PTN. However, it has remained unclear how β-catenin's function as a transcriptional activator with TCF1 influences mESC fate. Here, we show that TCF1-mediated transcription is up-regulated in differentiating mESCs and that chemical inhibition of β-catenin/TCF1 interaction improves long-term self-renewal and enhances functional pluripotency. Genetic loss of TCF1 inhibited differentiation by delaying exit from pluripotency and conferred a transcriptional profile strikingly reminiscent of self-renewing mESCs with high Nanog expression. Together, our data suggest that β-catenin's function in regulating mESCs is highly context specific and that its interaction with TCF1 promotes differentiation, further highlighting the need for understanding how its individual protein-protein interactions drive stem cell fate.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Cancer Institute, New York University Langone Medical Center, New York, NY 10016.
authors.forename: Sujash S
authors.initials: SS
authors.lastname: Chatterjee
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672.
authors.forename: Abil
authors.initials: A
authors.lastname: Saj
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Cancer Institute, New York University Langone Medical Center, New York, NY 10016.
authors.forename: Tenzin
authors.initials: T
authors.lastname: Gocha
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Cancer Institute, New York University Langone Medical Center, New York, NY 10016.
authors.forename: Matthew
authors.initials: M
authors.lastname: Murphy
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Cancer Institute, New York University Langone Medical Center, New York, NY 10016.
authors.forename: Foster C
authors.initials: FC
authors.lastname: Gonsalves
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, England, UK.
authors.forename: Penelope
authors.initials: P
authors.lastname: Hayward
authors.affiliation: Bioinformatics Core, New York University Langone Medical Center, New York, NY 10016.
authors.forename: Betül
authors.initials: B
authors.lastname: Akgöl Oksuz
authors.affiliation: Bioinformatics Core, New York University Langone Medical Center, New York, NY 10016.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Shen
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853.
authors.forename: Aviv
authors.initials: A
authors.lastname: Madar
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, England, UK.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Martinez Arias
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Cancer Institute, New York University Langone Medical Center, New York, NY 10016 Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672.
authors.forename: Ramanuj
authors.initials: R
authors.lastname: DasGupta
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D000066673:Cell Self Renewal; D002478:Cells, Cultured; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000502:physiology*; D010080:Oxazoles / Q000494:pharmacology; D014158:Transcription, Genetic; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D010080:Oxazoles; D051176:beta Catenin; C000604582:iCRT3 compound