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

  1. Shreyasi Mukherjee
  2. Praneet Chatuverdi
  3. Scott A Rankin
  4. Margaret B Fish
  5. Marcin Wlizla
  6. Kitt D Paraiso
  7. Melissa MacDonald
  8. Xiaoting Chen
  9. Matthew T Weirauch
  10. Ira L Blitz
  11. Ken WY Cho
  12. Aaron M Zorn  Is a corresponding author
  1. Cincinnati Children's Hospital Medical Center, United States
  2. University of California, Irvine, United States
Research Article
  • Cited 2
  • Views 1,927
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Cite this article as: eLife 2020;9:e58029 doi: 10.7554/eLife.58029

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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Shreyasi Mukherjee

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Praneet Chatuverdi

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Scott A Rankin

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Margaret B Fish

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Marcin Wlizla

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kitt D Paraiso

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Melissa MacDonald

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Xiaoting Chen

    Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Matthew T Weirauch

    Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Ira L Blitz

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Ken WY Cho

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Aaron M Zorn

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    For correspondence
    aaron.zorn@cchmc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3217-3590

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.

Reviewing Editor

  1. Carole LaBonne, Northwestern University, United States

Publication history

  1. Received: April 17, 2020
  2. Accepted: September 4, 2020
  3. Accepted Manuscript published: September 7, 2020 (version 1)
  4. Accepted Manuscript updated: September 8, 2020 (version 2)
  5. Version of Record published: September 17, 2020 (version 3)

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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