Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β-catenin recruitment to cis-regulatory modules

Yukio Nakamura, Eduardo de Paiva Alves, Gert Jan C. Veenstra, Stefan Hoppler

Research output: Contribution to journalArticle

45 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)1914-1925
Number of pages12
JournalDevelopment
Volume143
Issue number11
Early online date11 Apr 2016
DOIs
Publication statusPublished - 1 Jun 2016

Fingerprint

Catenins
Gene Expression
Genes
Response Elements
Proxy
Transcriptome
Transcriptional Activation
Chromatin
Embryonic Development
Homeostasis
Stem Cells
Genome

Keywords

  • Wnt signalling
  • β-catenin
  • Xenopus
  • Gastrula
  • ChIP-seq
  • RNA-seq

Cite this

Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β-catenin recruitment to cis-regulatory modules. / Nakamura, Yukio; de Paiva Alves, Eduardo; Veenstra, Gert Jan C.; Hoppler, Stefan.

In: Development, Vol. 143, No. 11, 01.06.2016, p. 1914-1925.

Research output: Contribution to journalArticle

Nakamura, Yukio ; de Paiva Alves, Eduardo ; Veenstra, Gert Jan C. ; Hoppler, Stefan. / Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β-catenin recruitment to cis-regulatory modules. In: Development. 2016 ; Vol. 143, No. 11. pp. 1914-1925.
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note = "Acknowledgements We thank Saartje Hontelez (Radboud University, Nijmegen), Sylvie Janssens and Kris Vleminckx (Vlaams Instituut voor Biotechnologie, Universiteit Gent) and Shelby Blythe (Princeton University) for advice on ChIP experiments; Caroline Hill (CRUK, LRI) for discussion on BMP signalling; Juan Larra{\'i}n (Pontificia Universitad Cat{\'o}lica de Chile) and Susan Fairley (European Bioinformatics Institute) for advice on RNA-seq experiments; Yvonne Turnbull (IMSARU, University of Aberdeen) for technical assistance; Alasdair MacKenzie (University of Aberdeen) for discussion and suggestions on the manuscript; Hajime Ogino (Nagahama Institute of Bio-Science and Technology) and Atsushi Suzuki (Hiroshima University) for plasmids; Pierre McCrea (University of Texas MD Anderson Cancer Center) for anti-Xenopus β-catenin antibody; The Genome Analysis Centre (TGAC, BBSRC, Norwich) for high-throughput sequencing; and Xenbase (http://www.xenbase.org) for reference database access. Funding This work was supported by the Biotechnology and Biological Sciences Research Council [BB/I003746/1 to S.H., BB/M001695/1 to S.H. and Y.N.]. Deposited in PMC for immediate release.",
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N1 - Acknowledgements We thank Saartje Hontelez (Radboud University, Nijmegen), Sylvie Janssens and Kris Vleminckx (Vlaams Instituut voor Biotechnologie, Universiteit Gent) and Shelby Blythe (Princeton University) for advice on ChIP experiments; Caroline Hill (CRUK, LRI) for discussion on BMP signalling; Juan Larraín (Pontificia Universitad Católica de Chile) and Susan Fairley (European Bioinformatics Institute) for advice on RNA-seq experiments; Yvonne Turnbull (IMSARU, University of Aberdeen) for technical assistance; Alasdair MacKenzie (University of Aberdeen) for discussion and suggestions on the manuscript; Hajime Ogino (Nagahama Institute of Bio-Science and Technology) and Atsushi Suzuki (Hiroshima University) for plasmids; Pierre McCrea (University of Texas MD Anderson Cancer Center) for anti-Xenopus β-catenin antibody; The Genome Analysis Centre (TGAC, BBSRC, Norwich) for high-throughput sequencing; and Xenbase (http://www.xenbase.org) for reference database access. Funding This work was supported by the Biotechnology and Biological Sciences Research Council [BB/I003746/1 to S.H., BB/M001695/1 to S.H. and Y.N.]. Deposited in PMC for immediate release.

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N2 - 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.

AB - 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.

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KW - β-catenin

KW - Xenopus

KW - Gastrula

KW - ChIP-seq

KW - RNA-seq

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