TY - JOUR T1 - Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks JF - bioRxiv DO - 10.1101/2020.03.13.990481 SP - 2020.03.13.990481 AU - Kelsey H. Elliott AU - Xiaoting Chen AU - Joseph Salomone AU - Praneet Chaturvedi AU - Preston A. Schultz AU - Sai K. Balchand AU - Jeffrey D. Servetas AU - Aimée Zuniga AU - Rolf Zeller AU - Brian Gebelein AU - Matthew T. Weirauch AU - Kevin A. Peterson AU - Samantha A. Brugmann Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/03/15/2020.03.13.990481.abstract N2 - 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. We demonstrated that rather than being driven by a Hh threshold, robust Gli3 transcriptional activity during skeletal and glossal development required interaction with the bHLH TF Hand2. Not only did genetic and expression data support a co-factorial relationship, but genomic analysis further 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. ER -