Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks.
Elife, 2020/10/02;9
Elliott KH[1, 2, 3], Chen X[4], Salomone J[1, 3, 5], Chaturvedi P[1], Schultz PA[1, 2], Balchand SK[1, 2], Servetas JD[6], Zuniga A[7], Zeller R[7], Gebelein B[1], Weirauch MT[1, 4], Peterson KA[6], Brugmann SA[1, 2, 8]
Affiliations
PMID: 33006313
Impact factor: 8.713
Abstract
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.
Keywords: Gli transcription factors; Hand2; cis-regulatory modules; developmental biology; functional genomic; low affinity binding; mandible; mouse
MeSH terms
Animals; Basic Helix-Loop-Helix Transcription Factors; Female; Male; Maxillofacial Development; Mice; Models, Animal; Nerve Tissue Proteins; Skull; Zinc Finger Protein Gli3
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