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

Abstract

Developmental signalling pathways operate repeatedly to regulate remarkably tissue- and stage-specific transcriptional responses. Canonical Wnt/β‑catenin signalling is such a key developmental pathway; however, while recruitment of nuclear β-catenin to target genomic loci serves as the hallmark of canonical Wnt signalling, mechanisms controlling context-specific transcriptional responses in different stages and tissues remain elusive. Here using the first direct comparison of genome-wide occupancy of β‑catenin with a stage-matched Wnt-regulated transcriptome in early vertebrate embryos, we discover that just a subset of β‑catenin-bound genomic loci are transcriptionally regulated by Wnt signalling. We further demonstrate that Wnt signalling regulates β‑catenin binding to Wnt target genes not only in the developmental context in which they are transcriptionally regulated, but also in other contexts, where their transcription remains unaffected. Their transcriptional response to Wnt signalling is conditional on additional mechanisms, such as BMP or FGF signalling for the particular genes we investigated, which, however, do not influence β‑catenin recruitment. In conclusion, our findings suggest a more general paradigm for Wnt-regulated transcriptional mechanisms, which is relevant for the repeated and tissue-specific functions of Wnt/β‑catenin signalling particularly 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 transcriptional Wnt target genes. Context-dependent mechanisms are crucial for transcriptional activation of Wnt/β‑catenin target genes subsequent to β‑catenin recruitment. Our conclusions therefore imply that Wnt-regulated β‑catenin binding in one context can mark Wnt-regulated transcriptional target genes for different contexts.