1. Developmental Biology
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Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks

  1. Kelsey H Elliott
  2. Xiaoting Chen
  3. Joseph Salomone
  4. Praneet Chaturvedi
  5. Preston A Schultz
  6. Sai K Balchand
  7. Jeffrey D Servetas
  8. Aimée zuniga
  9. Rolf Zeller
  10. Brian Gebelein
  11. Matthew T Weirauch
  12. Kevin A Peterson  Is a corresponding author
  13. Samantha A Brugmann  Is a corresponding author
  1. Cincinnati Children's Hospital Medical Center, United States
  2. The Jackson Laboratory, United States
  3. University of Basel, Switzerland
  4. Harvard University, United States
Research Article
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Cite this article as: eLife 2020;9:e56450 doi: 10.7554/eLife.56450

Abstract

Despite a common understanding that Gli TFs are utilized to reiterate a Hh morphogen gradient, genetic analyses suggest craniofacial development does not completely fit this paradigm. Using the mouse model (Mus musculus), we demonstrated that rather than being driven by a Hh threshold, robust Gli3 transcriptional activity during skeletal and glossal development required interaction with the basic helix-loop-helix TF Hand2. Not only did genetic and expression data support a co-factorial relationship, but genomic analysis revealed that Gli3 and Hand2 were enriched at regulatory elements for genes essential for mandibular patterning and development. Interestingly, motif analysis at sites co-occupied by Gli3 and Hand2 uncovered mandibular-specific, low-affinity, 'divergent' Gli binding motifs (<strong>d</strong>GBMs). Functional validation revealed these <strong>d</strong>GBMs conveyed synergistic activation of Gli targets essential for mandibular patterning and development. In summary, this work elucidates a novel, sequence-dependent mechanism for Gli transcriptional activity within the craniofacial complex that is independent of a graded Hh signal.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE141431, GSE141173.ChIP data have been deposited in GEO under accession code GSE146961All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1,5,8,9, Figure 1-figure supplement 1, Figure 8-figure supplement 2, and Figure 9-figure supplement 1

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

Article and author information

Author details

  1. Kelsey H Elliott

    Pediatrics - Division of Developmental Biology; Surgery- Division of Plastic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. 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.
  3. Joseph Salomone

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

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

    Pediatrics - Division of Developmental Biology; Surgery- Division of Plastic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sai K Balchand

    Pediatrics - Division of Developmental Biology; Surgery- Division of Plastic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jeffrey D Servetas

    The Jackson Laboratory, The Jackson Laboratory, Bar Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Aimée zuniga

    University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  9. Rolf Zeller

    University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  10. Brian Gebelein

    Pediatrics - Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9791-9061
  11. 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.
  12. Kevin A Peterson

    Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States
    For correspondence
    kevin.peterson@jax.org
    Competing interests
    The authors declare that no competing interests exist.
  13. Samantha A Brugmann

    Pediatrics - Division of Developmental Biology; Surgery- Division of Plastic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    For correspondence
    samantha.brugmann@cchmc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6860-6450

Funding

National Institutes of Health (R35DE027557)

  • Samantha A Brugmann

National Institutes of Health (R01GM124251)

  • Kevin A Peterson

National Institutes of Health (F31DE027872)

  • Kelsey H Elliott

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) protocols (IACUC2017-0063) of Cincinnati Children's Hospital Medical Center.

Reviewing Editor

  1. Kathryn Song Eng Cheah, The University of Hong Kong, Hong Kong

Publication history

  1. Received: February 27, 2020
  2. Accepted: October 1, 2020
  3. Accepted Manuscript published: October 2, 2020 (version 1)
  4. Version of Record published: October 14, 2020 (version 2)

Copyright

© 2020, Elliott 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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