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

eLife 2020 Oct 02

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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. © 2020, Elliott et al.

Citation

Kelsey H Elliott, Xiaoting Chen, Joseph Salomone, Praneet Chaturvedi, Preston A Schultz, Sai K Balchand, Jeffrey D Servetas, Aimée Zuniga, Rolf Zeller, Brian Gebelein, Matthew T Weirauch, Kevin A Peterson, Samantha A Brugmann. Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks. eLife. 2020 Oct 02;9