Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network
- Cincinnati Children's Hospital Medical Center, United States
- University of California, Irvine, United States
Abstract
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.
Data availability
The RNA-seq and ChIP-seq data generated by this study have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession GSE148726.
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Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endodermal gene regulatory networkNCBI Gene Expression Omnibus, GSE148726.
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Regional expression of X. tropicalis transcription factors in early gastrula embryosNCBI Gene Expression Omnibus, GSE81458.
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Foxh1 marks the embryonic genome prior to the activation of the mesendoderm gene regulatory programNCBI Gene Expression Omnibus, GSE85273.
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Enhancer chromatin signatures predict Smad2/3 binding in XenopusNCBI Gene Expression Omnibus, GSE56000.
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Embryonic transcription is controlled by maternally defined chromatin stateNCBI Gene Expression Omnibus, GSE67974.
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Transcription factor binding dynamics during human ES cell differentiationNCBI Gene Expression Omnibus, GSE61475.
Article and author information
Author details
Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD073179)
- Aaron M Zorn
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK078392)
- Aaron M Zorn
Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD073179)
- Ken WY Cho
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (#AU2_IACUC2016-0059) of the Cincinnati Children's Hospital Medical Center.
Copyright
© 2020, Mukherjee et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network
eLife 9:e58029.
https://doi.org/10.7554/eLife.58029
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