Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks
- Cincinnati Children's Hospital Medical Center, United States
- The Jackson Laboratory, United States
- University of Basel, Switzerland
- Harvard University, United States
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
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Single cell sequencing of dissected mouse mandibular prominence at embryonic day e11.5 and e13.5NCBI Gene Expression Omnibus, GSE141173.
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Gli3 and Hand2 ChIP-sequencing of developing face and mandibular prominenceNCBI Gene Expression Omnibus, GSE146961.
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Genome-wide candidate HAND2 target regions in mouse embryonic tissuesNCBI Gene Expression Omnibus, GSE55707.
Article and author information
Author details
Samantha A Brugmann
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
- Kathryn Song Eng Cheah, The University of Hong Kong, Hong Kong
Version history
- Received: February 27, 2020
- Accepted: October 1, 2020
- Accepted Manuscript published: October 2, 2020 (version 1)
- 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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Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks
eLife 9:e56450.
https://doi.org/10.7554/eLife.56450
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