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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...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
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
Descripción
Sumario: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.