title: Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β-catenin recruitment to cis-regulatory modules.
abstract: Key signalling pathways, such as canonical Wnt/β-catenin signalling, operate repeatedly to regulate tissue- and stage-specific transcriptional responses during development. Although recruitment of nuclear β-catenin to target genomic loci serves as the hallmark of canonical Wnt signalling, mechanisms controlling stage- or tissue-specific transcriptional responses remain elusive. Here, a direct comparison of genome-wide occupancy of β-catenin with a stage-matched Wnt-regulated transcriptome reveals that only a subset of β-catenin-bound genomic loci are transcriptionally regulated by Wnt signalling. We demonstrate that Wnt signalling regulates β-catenin binding to Wnt target genes not only when they are transcriptionally regulated, but also in contexts in which their transcription remains unaffected. The transcriptional response to Wnt signalling depends on additional mechanisms, such as BMP or FGF signalling for the particular genes we investigated, which do not influence β-catenin recruitment. Our findings suggest a more general paradigm for Wnt-regulated transcriptional mechanisms, which is relevant for tissue-specific functions of Wnt/β-catenin signalling in embryonic development but also for stem cell-mediated homeostasis and cancer. Chromatin association of β-catenin, even to functional Wnt-response elements, can no longer be considered a proxy for identifying transcriptionally Wnt-regulated genes. Context-dependent mechanisms are crucial for transcriptional activation of Wnt/β-catenin target genes subsequent to β-catenin recruitment. Our conclusions therefore also imply that Wnt-regulated β-catenin binding in one context can mark Wnt-regulated transcriptional target genes for different contexts.
authors.affiliation: Institute of Medical Sciences, Foresterhill Health Campus, University of Aberdeen, Aberdeen AB25 2ZD, UK.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Centre for Genome-Enabled Biology and Medicine, University of Aberdeen, Aberdeen AB24 3RY, UK.
authors.forename: Eduardo
authors.initials: E
authors.lastname: de Paiva Alves
authors.affiliation: Radboud University, Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands.
authors.forename: Gert Jan C
authors.initials: GJ
authors.lastname: Veenstra
authors.affiliation: Institute of Medical Sciences, Foresterhill Health Campus, University of Aberdeen, Aberdeen AB25 2ZD, UK s.p.hoppler@abdn.ac.uk.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hoppler
mesh_terms: D000818:Animals; D001483:Base Sequence; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D005775:Gastrula / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D056426:Genetic Loci; D016678:Genome; D008954:Models, Biological; D009928:Organ Specificity / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D059467:Transcriptome / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology / Q000235:genetics*; D029867:Xenopus Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D002843:Chromatin; D051153:Wnt Proteins; D029867:Xenopus Proteins; D051176:beta Catenin; C495248:wnt8a protein, Xenopus
keywords: ChIP-seq; Gastrula; RNA-seq; Wnt signalling; Xenopus; β-catenin