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Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif

Transcriptional regulation by Wnt signalling is primarily thought to be accomplished by a complex of β-catenin and TCF family transcription factors (TFs). Although numerous studies have suggested that additional TFs play roles in regulating Wnt target genes, their mechanisms of action have not been...

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Autores principales: Ramakrishnan, Aravinda-Bharathi, Chen, Lisheng, Burby, Peter E, Cadigan, Ken M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421206/
https://www.ncbi.nlm.nih.gov/pubmed/34358319
http://dx.doi.org/10.1093/nar/gkab657
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author Ramakrishnan, Aravinda-Bharathi
Chen, Lisheng
Burby, Peter E
Cadigan, Ken M
author_facet Ramakrishnan, Aravinda-Bharathi
Chen, Lisheng
Burby, Peter E
Cadigan, Ken M
author_sort Ramakrishnan, Aravinda-Bharathi
collection PubMed
description Transcriptional regulation by Wnt signalling is primarily thought to be accomplished by a complex of β-catenin and TCF family transcription factors (TFs). Although numerous studies have suggested that additional TFs play roles in regulating Wnt target genes, their mechanisms of action have not been investigated in detail. We characterised a Wnt-responsive element (WRE) downstream of the Wnt target gene Axin2 and found that TCFs and Caudal type homeobox (CDX) proteins were required for its activation. Using a new separation-of-function TCF mutant, we found that WRE activity requires the formation of a TCF/CDX complex. Our systematic mutagenesis of this enhancer identified other sequences essential for activation by Wnt signalling, including several copies of a novel CAG DNA motif. Computational and experimental evidence indicates that the TCF/CDX/CAG mode of regulation is prevalent in multiple WREs. Put together, our results demonstrate the complex nature of cis- and trans- interactions required for signal-dependent enhancer activity.
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spelling pubmed-84212062021-09-09 Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif Ramakrishnan, Aravinda-Bharathi Chen, Lisheng Burby, Peter E Cadigan, Ken M Nucleic Acids Res Gene regulation, Chromatin and Epigenetics Transcriptional regulation by Wnt signalling is primarily thought to be accomplished by a complex of β-catenin and TCF family transcription factors (TFs). Although numerous studies have suggested that additional TFs play roles in regulating Wnt target genes, their mechanisms of action have not been investigated in detail. We characterised a Wnt-responsive element (WRE) downstream of the Wnt target gene Axin2 and found that TCFs and Caudal type homeobox (CDX) proteins were required for its activation. Using a new separation-of-function TCF mutant, we found that WRE activity requires the formation of a TCF/CDX complex. Our systematic mutagenesis of this enhancer identified other sequences essential for activation by Wnt signalling, including several copies of a novel CAG DNA motif. Computational and experimental evidence indicates that the TCF/CDX/CAG mode of regulation is prevalent in multiple WREs. Put together, our results demonstrate the complex nature of cis- and trans- interactions required for signal-dependent enhancer activity. Oxford University Press 2021-08-06 /pmc/articles/PMC8421206/ /pubmed/34358319 http://dx.doi.org/10.1093/nar/gkab657 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Gene regulation, Chromatin and Epigenetics
Ramakrishnan, Aravinda-Bharathi
Chen, Lisheng
Burby, Peter E
Cadigan, Ken M
Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif
title Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif
title_full Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif
title_fullStr Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif
title_full_unstemmed Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif
title_short Wnt target enhancer regulation by a CDX/TCF transcription factor collective and a novel DNA motif
title_sort wnt target enhancer regulation by a cdx/tcf transcription factor collective and a novel dna motif
topic Gene regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421206/
https://www.ncbi.nlm.nih.gov/pubmed/34358319
http://dx.doi.org/10.1093/nar/gkab657
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