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Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks
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Journal Article
Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks
2020
Overview
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 ( d GBMs). Functional validation revealed these d GBMs 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.
Publisher
eLife Science Publications, Ltd,eLife Sciences Publications, Ltd,eLife Sciences Publications Ltd
Subject
/ Animals
/ Basic Helix-Loop-Helix Transcription Factors - genetics
/ Basic Helix-Loop-Helix Transcription Factors - metabolism
/ Female
/ Hand2
/ Male
/ mandible
/ Maxillofacial Development - genetics
/ Nerve Tissue Proteins - genetics
/ Nerve Tissue Proteins - metabolism
/ Skull - growth & development
