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Two-Element Transcriptional Regulation in the Canonical Wnt Pathway

Kim, Kibeom and Cho, Jaehyoung and Hilzinger, Thomas S. and Nunns, Harry and Liu, Andrew and Ryba, Bryan E. and Goentoro, Lea (2017) Two-Element Transcriptional Regulation in the Canonical Wnt Pathway. Current Biology, 27 (15). pp. 2357-2364. ISSN 0960-9822. PMCID PMC5557293. doi:10.1016/j.cub.2017.06.037.

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The canonical Wnt pathway regulates numerous fundamental processes throughout development and adult physiology and is often disrupted in diseases [1; 2; 3 ; 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.

Item Type:Article
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URLURL TypeDescription CentralArticle
Goentoro, Lea0000-0002-3904-0195
Additional Information:© 2017 Elsevier Ltd. Received 4 May 2017, Revised 2 June 2017, Accepted 14 June 2017, Available online 27 July 2017, Published: July 27, 2017. We wish to dedicate this paper to Eric H. Davidson (1937–2015). His singular vision, commitment to truth, and unwavering intellectual rigor kept us all vigilant. His inspiring presence is deeply missed. We thank Marc Kirschner, in whose lab the early part of this work was performed and for discussions afterward. We thank David Kimelman and Sergei Sokol for siamois promoter clones; Michael Klimkowsky for XTcf3 antibodies; Bil Clemons, Axel Müller, and Katrin Tiemann for pETKatN10 protein expression vector; and Hans Clevers, Jurian Schuijers, Michal Mokry, and Gregory Yochum for sharing their ChIP-seq data. We thank James Linton for advice on stem cell culture and CRISPR/Cas9 protocol. We thank Ellen Rothenberg, Ray Deshaies, Christopher Frick, and Michael Abrams for discussions. This work was supported by the NIH New Innovator Award (1DP2OD008471) to L.G., NIH Training Grant (5T32GM007616-37) to H.N., and Caltech’s SURF and Amgen Scholar to B.E.R. Author Contributions: J.C., T.S.H., K.K., A.L., B.E.R., and L.G. designed experiments, performed experiments, and performed data analysis. H.N. performed modeling analysis, contributed to data analysis, and wrote the model supplement. K.K. and L.G. wrote the manuscript.
Funding AgencyGrant Number
NIH Predoctoral Fellowship5T32GM007616-37
Caltech Summer Undergraduate Research Fellowship (SURF)UNSPECIFIED
AmGen Scholars ProgramUNSPECIFIED
Issue or Number:15
PubMed Central ID:PMC5557293
Record Number:CaltechAUTHORS:20170728-083017566
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Official Citation:Kibeom Kim, Jaehyoung Cho, Thomas S. Hilzinger, Harry Nunns, Andrew Liu, Bryan E. Ryba, Lea Goentoro, Two-Element Transcriptional Regulation in the Canonical Wnt Pathway, Current Biology, Volume 27, Issue 15, 7 August 2017, Pages 2357-2364.e5, ISSN 0960-9822,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:79527
Deposited By: Tony Diaz
Deposited On:28 Jul 2017 15:57
Last Modified:23 Mar 2022 19:57

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