XB-ART-52077Development 2016 Jun 01;14311:1914-25. doi: 10.1242/dev.131664.
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Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β-catenin recruitment to cis-regulatory modules.
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.
PubMed ID: 27068107
PMC ID: PMC4920159
Article link: Development
Species referenced: Xenopus
Genes referenced: atp12a axin1 axin2l cdk2 cdx2 cdx4 chrd.1 ctnnb1 frzb fst fzd10 gbx2.2 gsc homer1 hoxa1 hoxd1 msgn1 msx1 neurog1 nodal3.1 nodal3.4 nog sia1 sp5 ventx1.2 wnt8a
Antibodies: Ctnnb1 Ab2
Morpholinos: wnt8a MO5
GEO Series: GSE72657: Xenbase, NCBI
Phenotypes: Xla Wt + wnt8a MO (Fig.2 A III)
Article Images: [+] show captions
References [+] :
Abu-Remaileh, Oct-3/4 regulates stem cell identity and cell fate decisions by modulating Wnt/β-catenin signalling. 2010, Pubmed, Xenbase