Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β‑catenin recruitment.

Key signalling pathways, such as canonical Wnt/beta-catenin signalling, operate repeatedly to regulate tissue-and stage-specific transcriptional responses during development. Although recruitment of nuclear beta-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 beta-catenin with a stage-matched Wnt-regulated transcriptome reveals that only a subset of beta-catenin-bound genomic loci are transcriptionally regulated by Wnt signalling. We demonstrate that Wnt signalling regulates beta-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 beta-catenin recruitment. Our findings suggest a more general paradigm for Wnt-regulated transcriptional mechanisms, which is relevant for tissue-specific functions of Wnt/beta-catenin signalling in embryonic development but also for stem cell-mediated homeostasis and cancer. Chromatin association of beta-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/beta-catenin target genes subsequent to beta-catenin recruitment. Our conclusions therefore also imply that Wnt-regulated beta-catenin binding in one context can mark Wnt-regulated transcriptional target genes for different contexts.