title: Intrinsic properties of Tcf1 and Tcf4 splice variants determine cell-type-specific Wnt/β-catenin target gene expression.
abstract: T-cell factor (Tcf)/lymphoid-enhancer factor (Lef) proteins are a structurally diverse family of deoxyribonucleic acid-binding proteins that have essential nuclear functions in Wnt/β-catenin signalling. Expression of Wnt/β-catenin target genes is highly dependent on context, but the precise role of Tcf/Lef family members in the generation and maintenance of cell-type-specific Wnt/β-catenin responses is unknown. Herein, we show that induction of a subset of Wnt/β-catenin targets in embryonic stem cells depends on Tcf1 and Tcf4, whereas other co-expressed Tcf/Lef family members cannot induce these targets. The Tcf1/Tcf4-dependent gene responses to Wnt are primarily if not exclusively mediated by C-clamp-containing Tcf1E and Tcf4E splice variants. A combined knockdown of Tcf1/Tcf4 abrogates Wnt-inducible transcription but does not affect the active chromatin conformation of their targets. Thus, the transcriptionally poised state of Wnt/β-catenin targets is maintained independent of Tcf/Lef proteins. Conversely, ectopically overexpressed Tcf1E cannot invade silent chromatin and fails to initiate expression of inactive Wnt/β-catenin targets even if repressive chromatin modifications are abolished. The observed non-redundant functions of Tcf1/Tcf4 isoforms in acute transcriptional activation demonstrated that the cell-type-specific complement of Tcf/Lef proteins is a critical determinant of context-dependent Wnt/β-catenin responses. Moreover, the apparent inability to cope with chromatin uncovers an intrinsic property of Tcf/Lef proteins that prevents false ectopic induction and ensures spatiotemporal stability of Wnt/β-catenin target gene expression.
authors.affiliation: Spemann Graduate School of Biology and Medicine and Faculty of Biology, Albert-Ludwigs-University Freiburg, Albertstr. 19A, D-79104 Freiburg, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Wallmen
authors.forename: Monika
authors.initials: M
authors.lastname: Schrempp
authors.forename: Andreas
authors.initials: A
authors.lastname: Hecht
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry; D053595:Embryonic Stem Cells / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051822:T Cell Transcription Factor 1 / Q000235:genetics / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D060449:Wnt Signaling Pathway
chemical_list: D002843:Chromatin; D020033:Protein Isoforms; D051822:T Cell Transcription Factor 1; D058118:Transcription Factor 7-Like 2 Protein