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Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks
Despite a common understanding that Gli TFs are utilized to convey 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 tran...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556880/ https://www.ncbi.nlm.nih.gov/pubmed/33006313 http://dx.doi.org/10.7554/eLife.56450 |
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author | Elliott, Kelsey H Chen, Xiaoting Salomone, Joseph Chaturvedi, Praneet Schultz, Preston A Balchand, Sai K Servetas, Jeffrey D Zuniga, Aimée Zeller, Rolf Gebelein, Brian Weirauch, Matthew T Peterson, Kevin A Brugmann, Samantha A |
author_facet | Elliott, Kelsey H Chen, Xiaoting Salomone, Joseph Chaturvedi, Praneet Schultz, Preston A Balchand, Sai K Servetas, Jeffrey D Zuniga, Aimée Zeller, Rolf Gebelein, Brian Weirauch, Matthew T Peterson, Kevin A Brugmann, Samantha A |
author_sort | Elliott, Kelsey H |
collection | PubMed |
description | Despite a common understanding that Gli TFs are utilized to convey 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 (dGBMs). Functional validation revealed these dGBMs 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. |
format | Online Article Text |
id | pubmed-7556880 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-75568802020-10-16 Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks Elliott, Kelsey H Chen, Xiaoting Salomone, Joseph Chaturvedi, Praneet Schultz, Preston A Balchand, Sai K Servetas, Jeffrey D Zuniga, Aimée Zeller, Rolf Gebelein, Brian Weirauch, Matthew T Peterson, Kevin A Brugmann, Samantha A eLife Developmental Biology Despite a common understanding that Gli TFs are utilized to convey 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 (dGBMs). Functional validation revealed these dGBMs 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. eLife Sciences Publications, Ltd 2020-10-02 /pmc/articles/PMC7556880/ /pubmed/33006313 http://dx.doi.org/10.7554/eLife.56450 Text en © 2020, Elliott et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Developmental Biology Elliott, Kelsey H Chen, Xiaoting Salomone, Joseph Chaturvedi, Praneet Schultz, Preston A Balchand, Sai K Servetas, Jeffrey D Zuniga, Aimée Zeller, Rolf Gebelein, Brian Weirauch, Matthew T Peterson, Kevin A Brugmann, Samantha A Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks |
title | Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks |
title_full | Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks |
title_fullStr | Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks |
title_full_unstemmed | Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks |
title_short | Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks |
title_sort | gli3 utilizes hand2 to synergistically regulate tissue-specific transcriptional networks |
topic | Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556880/ https://www.ncbi.nlm.nih.gov/pubmed/33006313 http://dx.doi.org/10.7554/eLife.56450 |
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