1. Developmental Biology
Download icon

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 8
  • Views 2,494
  • Annotations
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.

Metrics

  • 2,494
    Page views
  • 355
    Downloads
  • 8
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Developmental Biology
    2. Neuroscience
    David Sokolov et al.
    Research Article

    Despite mounting evidence that the mammalian retina is exceptionally reliant on proper NAD+ homeostasis for health and function, the specific roles of subcellular NAD+ pools in retinal development, maintenance, and disease remain obscure. Here, we show that deletion of the nuclear-localized NAD+ synthase nicotinamide mononucleotide adenylyltransferase-1 (NMNAT1) in the developing murine retina causes early and severe degeneration of photoreceptors and select inner retinal neurons via multiple distinct cell death pathways. This severe phenotype is associated with disruptions to retinal central carbon metabolism, purine nucleotide synthesis, and amino acid pathways. Furthermore, transcriptomic and immunostaining approaches reveal dysregulation of a collection of photoreceptor and synapse-specific genes in NMNAT1 knockout retinas prior to detectable morphological or metabolic alterations. Collectively, our study reveals previously unrecognized complexity in NMNAT1-associated retinal degeneration and suggests a yet-undescribed role for NMNAT1 in gene regulation during photoreceptor terminal differentiation.

    1. Developmental Biology
    2. Neuroscience
    Nishtha Ranawat, Ichiro Masai
    Research Article

    Microglia are brain-resident macrophages that function as the first line of defense in brain. Embryonic microglial precursors originate in peripheral mesoderm and migrate into the brain during development. However, the mechanism by which they colonize the brain is incompletely understood. The retina is one of the first brain regions to accommodate microglia. In zebrafish, embryonic microglial precursors use intraocular hyaloid blood vessels as a pathway to migrate into the optic cup via the choroid fissure. Once retinal progenitor cells exit the cell cycle, microglial precursors associated with hyaloid blood vessels start to infiltrate the retina preferentially through neurogenic regions, suggesting that colonization of retinal tissue depends upon the neurogenic state. Along with blood vessels and retinal neurogenesis, IL34 also participates in microglial precursor colonization of the retina. Altogether, CSF receptor signaling, blood vessels, and neuronal differentiation function as cues to create an essential path for microglial migration into developing retina.