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Curr Biol 2017 Aug 07;2715:2357-2364.e5. doi: 10.1016/j.cub.2017.06.037.
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Two-Element Transcriptional Regulation in the Canonical Wnt Pathway.

Kim K , Cho J , Hilzinger TS , Nunns H , Liu A , Ryba BE , Goentoro L .

The canonical Wnt pathway regulates numerous fundamental processes throughout development and adult physiology and is often disrupted in diseases [1-4]. Signal in the pathway is transduced by β-catenin, which in complex with Tcf/Lef regulates transcription. Despite the many processes that the Wnt pathway governs, β-catenin acts primarily on a single cis element in the DNA, the Wnt-responsive element (WRE), at times potentiated by a nearby Helper site. In this study, working with Xenopus, mouse, and human systems, we identified a cis element, distinct from WRE, upon which β-catenin and Tcf act. The element is 11 bp long, hundreds of bases apart from the WRE, and exhibits a suppressive effect. In Xenopus patterning, loss of the 11-bp negative regulatory elements (11-bp NREs) broadened dorsal expression of siamois. In mouse embryonic stem cells, genomic deletion of the 11-bp NREs in the promoter elevated Brachyury expression. This reveals a previously unappreciated mechanism within the Wnt pathway, where gene response is not only driven by WREs but also tuned by 11-bp NREs. Using electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP), we found evidence for the NREs binding to β-catenin and Tcf-suggesting a dual action by β-catenin as a signal and a feedforward sensor. Analyzing β-catenin ChIP sequencing in human cells, we found the 11-bp NREs co-localizing with the WRE in 45%-71% of the peaks, suggesting a widespread role for the mechanism. This study presents an example of a more complex cis regulation by a signaling pathway, where a signal is processed through two distinct cis elements in a gene circuitry.

PubMed ID: 28756947
PMC ID: PMC5557293
Article link: Curr Biol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: axin2 cdx4 ctnnb1 en1 gsk3b nodal3.1 nodal3.2 prl.2 rps3a sia1 tbxt tcf3 tp53
Antibodies: Ctnnb1 Ab11

Article Images: [+] show captions
References [+] :
Anastas, WNT signalling pathways as therapeutic targets in cancer. 2012, Pubmed