Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks

Elliott, K. H.; Chen, X.; Salomone, J.; Chatuverdi, P.; Schultz, P. A.; Balchand, S. K.; Servetas, J. D.; Zuniga, A.; Zeller, R.; Gebelein, B.; Weirauch, M. T.; Peterson, K. A.; Brugmann, S. A.

doi:10.1101/2020.03.13.990481

bioRxiv · 10.1101/2020.03.13.990481

Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks

Elliott, K. H.·Chen, X.·Salomone, J.·Chatuverdi, P.·Schultz, P. A.·Balchand, S. K.·Servetas, J. D.·Zuniga, A.·Zeller, R.·Gebelein, B.·Weirauch, M. T.·Peterson, K. A.·Brugmann, S. A.

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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. 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.

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Elliott, K. H., Chen, X., Salomone, J., Chatuverdi, P., Schultz, P. A., Balchand, S. K., Servetas, J. D., Zuniga, A., Zeller, R., Gebelein, B., Weirauch, M. T., Peterson, K. A., Brugmann, S. A.. 2020-03-15. Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks. https://doi.org/10.1101/2020.03.13.990481

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