title: Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal.
abstract: The co-occupancy of Tcf3 with Oct4, Sox2 and Nanog on embryonic stem cell (ESC) chromatin indicated that Tcf3 has been suggested to play an integral role in a poorly understood mechanism underlying Wnt-dependent stimulation of mouse ESC self-renewal of mouse ESCs. Although the conventional view of Tcf proteins as the β-catenin-binding effectors of Wnt signalling suggested Tcf3-β-catenin activation of target genes would stimulate self-renewal, here we show that an antagonistic relationship between Wnt3a and Tcf3 on gene expression regulates ESC self-renewal. Genetic ablation of Tcf3 replaced the requirement for exogenous Wnt3a or GSK3 inhibition for ESC self-renewal, demonstrating that inhibition of Tcf3 repressor is the necessary downstream effect of Wnt signalling. Interestingly, both Tcf3-β-catenin and Tcf1-β-catenin interactions contributed to Wnt stimulation of self-renewal and gene expression, and the combination of Tcf3 and Tcf1 recruited Wnt-stabilized β-catenin to Oct4 binding sites on ESC chromatin. This work elucidates the molecular link between the effects of Wnt and the regulation of the Oct4/Sox2/Nanog network.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 S Ashland Avenue, MBRB 2270, M/C 669, Chicago, Illinois 60607, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Yi
authors.forename: Laura
authors.initials: L
authors.lastname: Pereira
authors.forename: Jackson A
authors.initials: JA
authors.lastname: Hoffman
authors.forename: Brian R
authors.initials: BR
authors.lastname: Shy
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Yuen
authors.forename: David R
authors.initials: DR
authors.lastname: Liu
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Merrill
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D038362:Glycogen Synthase Kinase 3; D051538:Hepatocyte Nuclear Factor 1-alpha; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D047428:Protein Kinase Inhibitors; D055748:SOXB1 Transcription Factors; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin; C495267:CTNNB1 protein, mouse; C496488:Hnf1a protein, mouse; C475540:Nanog protein, mouse; C494174:Pou5f1 protein, mouse; C527783:Sox2 protein, mouse; C075668:Tcf3 protein, mouse; C555511:Wnt3a protein, mouse