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.
Highlights
Key signalling mechanisms are deployed repeatedly during embryonic development to regulate differential gene expression, often in combination with each other and with other regulatory mechanisms
Β-catenin regulates target gene expression in association with DNA-binding proteins, those of the TCF/LEF family. β-catenin ChIP-seq analysis had been used to identify direct transcriptional targets of Wnt signalling in cancer tissue and cultured cells (Bottomly et al, 2010; Park et al, 2012; Schuijers et al, 2014; Watanabe et al, 2014)
Β-catenin ChIP analysis in the same experiment revealed differences among maternal Wnt-regulated gene loci; for some, levels of β-catenin binding were increased by experimentally enhanced Wnt8a activity in gastrula embryos (Fig. 4D, green), similar to wnt8a targets; whereas others were neither associated with endogenous β-catenin nor with experimentally activated β-catenin in gastrula embryos (Fig. 4D; see Table S4 for β-peaks of maternal Wntregulated gene loci). These results demonstrate in two different developmental contexts that Wnt-regulated β-catenin association is not sufficient for transcriptional activation
Summary
Key signalling mechanisms are deployed repeatedly during embryonic development to regulate differential gene expression, often in combination with each other and with other regulatory mechanisms. Wnt/β-catenin signalling (hereafter referred to as Wnt signalling) is an important, evolutionarily conserved cell-to-cell signalling mechanism that regulates the transcription of specific. The developmental, cellular and transcriptional responses to Wnt signalling are often remarkably specific for particular stages, tissues and cell lineages, and the molecular mechanisms by which the specific Wnt/β-catenin target genes are regulated in different cellular and developmental contexts are still largely unknown. Characterising these context-specific mechanisms is important for understanding the specific functional roles of Wnt signalling in embryonic development and disease
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