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Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network

Lineage specification is governed by gene regulatory networks (GRNs) that integrate the activity of signaling effectors and transcription factors (TFs) on enhancers. Sox17 is a key transcriptional regulator of definitive endoderm development, and yet, its genomic targets remain largely uncharacteriz...

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Autores principales: Mukherjee, Shreyasi, Chaturvedi, Praneet, Rankin, Scott A, Fish, Margaret B, Wlizla, Marcin, Paraiso, Kitt D, MacDonald, Melissa, Chen, Xiaoting, Weirauch, Matthew T, Blitz, Ira L, Cho, Ken WY, Zorn, Aaron M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498262/
https://www.ncbi.nlm.nih.gov/pubmed/32894225
http://dx.doi.org/10.7554/eLife.58029
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author Mukherjee, Shreyasi
Chaturvedi, Praneet
Rankin, Scott A
Fish, Margaret B
Wlizla, Marcin
Paraiso, Kitt D
MacDonald, Melissa
Chen, Xiaoting
Weirauch, Matthew T
Blitz, Ira L
Cho, Ken WY
Zorn, Aaron M
author_facet Mukherjee, Shreyasi
Chaturvedi, Praneet
Rankin, Scott A
Fish, Margaret B
Wlizla, Marcin
Paraiso, Kitt D
MacDonald, Melissa
Chen, Xiaoting
Weirauch, Matthew T
Blitz, Ira L
Cho, Ken WY
Zorn, Aaron M
author_sort Mukherjee, Shreyasi
collection PubMed
description Lineage specification is governed by gene regulatory networks (GRNs) that integrate the activity of signaling effectors and transcription factors (TFs) on enhancers. Sox17 is a key transcriptional regulator of definitive endoderm development, and yet, its genomic targets remain largely uncharacterized. Here, using genomic approaches and epistasis experiments, we define the Sox17-governed endoderm GRN in Xenopus gastrulae. We show that Sox17 functionally interacts with the canonical Wnt pathway to specify and pattern the endoderm while repressing alternative mesectoderm fates. Sox17 and β-catenin co-occupy hundreds of key enhancers. In some cases, Sox17 and β-catenin synergistically activate transcription apparently independent of Tcfs, whereas on other enhancers, Sox17 represses β-catenin/Tcf-mediated transcription to spatially restrict gene expression domains. Our findings establish Sox17 as a tissue-specific modifier of Wnt responses and point to a novel paradigm where genomic specificity of Wnt/β-catenin transcription is determined through functional interactions between lineage-specific Sox TFs and β-catenin/Tcf transcriptional complexes. Given the ubiquitous nature of Sox TFs and Wnt signaling, this mechanism has important implications across a diverse range of developmental and disease contexts.
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spelling pubmed-74982622020-09-21 Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network Mukherjee, Shreyasi Chaturvedi, Praneet Rankin, Scott A Fish, Margaret B Wlizla, Marcin Paraiso, Kitt D MacDonald, Melissa Chen, Xiaoting Weirauch, Matthew T Blitz, Ira L Cho, Ken WY Zorn, Aaron M eLife Developmental Biology Lineage specification is governed by gene regulatory networks (GRNs) that integrate the activity of signaling effectors and transcription factors (TFs) on enhancers. Sox17 is a key transcriptional regulator of definitive endoderm development, and yet, its genomic targets remain largely uncharacterized. Here, using genomic approaches and epistasis experiments, we define the Sox17-governed endoderm GRN in Xenopus gastrulae. We show that Sox17 functionally interacts with the canonical Wnt pathway to specify and pattern the endoderm while repressing alternative mesectoderm fates. Sox17 and β-catenin co-occupy hundreds of key enhancers. In some cases, Sox17 and β-catenin synergistically activate transcription apparently independent of Tcfs, whereas on other enhancers, Sox17 represses β-catenin/Tcf-mediated transcription to spatially restrict gene expression domains. Our findings establish Sox17 as a tissue-specific modifier of Wnt responses and point to a novel paradigm where genomic specificity of Wnt/β-catenin transcription is determined through functional interactions between lineage-specific Sox TFs and β-catenin/Tcf transcriptional complexes. Given the ubiquitous nature of Sox TFs and Wnt signaling, this mechanism has important implications across a diverse range of developmental and disease contexts. eLife Sciences Publications, Ltd 2020-09-07 /pmc/articles/PMC7498262/ /pubmed/32894225 http://dx.doi.org/10.7554/eLife.58029 Text en © 2020, Mukherjee et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Developmental Biology
Mukherjee, Shreyasi
Chaturvedi, Praneet
Rankin, Scott A
Fish, Margaret B
Wlizla, Marcin
Paraiso, Kitt D
MacDonald, Melissa
Chen, Xiaoting
Weirauch, Matthew T
Blitz, Ira L
Cho, Ken WY
Zorn, Aaron M
Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network
title Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network
title_full Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network
title_fullStr Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network
title_full_unstemmed Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network
title_short Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network
title_sort sox17 and β-catenin co-occupy wnt-responsive enhancers to govern the endoderm gene regulatory network
topic Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498262/
https://www.ncbi.nlm.nih.gov/pubmed/32894225
http://dx.doi.org/10.7554/eLife.58029
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