title: Convergence of cMyc and β-catenin on Tcf7l1 enables endoderm specification.
abstract: The molecular machinery that directs formation of definitive endoderm from pluripotent stem cells is not well understood. Wnt/β-catenin and Nodal signalling have been implicated, but the requirements for lineage specification remain incompletely defined. Here, we demonstrate a potent effect of inhibiting glycogen synthase kinase 3 (GSK3) on definitive endoderm production. We find that downstream of GSK3 inhibition, elevated cMyc and β-catenin act in parallel to reduce transcription and DNA binding, respectively, of the transcriptional repressor Tcf7l1. Tcf7l1 represses FoxA2, a pioneer factor for endoderm specification. Deletion of Tcf7l1 is sufficient to allow upregulation of FoxA2 in the presence of Activin. In wild-type cells, cMyc contributes by reducing Tcf7l1 mRNA, while β-catenin acts on Tcf7l1 protein. GSK3 inhibition is further required for consolidation of endodermal fate via upregulation of Sox17, highlighting sequential roles for Wnt signalling. The identification of a cMyc/β-catenin-Tcf7l1-FoxA2 axis reveals a de-repression mechanism underlying endoderm induction that may be recapitulated in other developmental and patho-logical contexts.
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK gillian.morrison@ed.ac.uk austin.smith@cscr.cam.ac.uk.
authors.forename: Gillian
authors.initials: G
authors.lastname: Morrison
authors.affiliation: Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
authors.forename: Roberta
authors.initials: R
authors.lastname: Scognamiglio
authors.affiliation: Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK Department of Biochemistry, University of Cambridge, Cambridge, UK gillian.morrison@ed.ac.uk austin.smith@cscr.cam.ac.uk.
authors.forename: Austin
authors.initials: A
authors.lastname: Smith
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000502:physiology; D004707:Endoderm / Q000254:growth & development*; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction; D058125:Transcription Factor 7-Like 1 Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C496503:Foxa2 protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C544913:Tcf7l1 protein, mouse; D058125:Transcription Factor 7-Like 1 Protein; D051176:beta Catenin; D028341:Activins; D051542:Hepatocyte Nuclear Factor 3-beta; D038362:Glycogen Synthase Kinase 3
keywords: FoxA2; Myc; Tcf7l1; embryonic stem cells; endoderm