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Gli3 通过与 Hand2 协同作用来调节组织特异性转录网络。

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

机构信息

Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States.

Division of Plastic Surgery, Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, United States.

出版信息

Elife. 2020 Oct 2;9:e56450. doi: 10.7554/eLife.56450.

DOI:10.7554/eLife.56450
PMID:33006313
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7556880/
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 (), 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 (GBMs). Functional validation revealed these 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.

摘要

尽管人们普遍认为 Gli TFs 用于传递 Hh 形态发生梯度，但遗传分析表明颅面发育并不完全符合这一模式。使用小鼠模型（），我们证明，在骨骼和舌部发育过程中，Gli3 转录活性的增强不是由 Hh 阈值驱动的，而是需要与碱性螺旋-环-螺旋 TF Hand2 相互作用。不仅遗传和表达数据支持共同因子关系，而且基因组分析表明，Gli3 和 Hand2 富集在调控元件上，这些调控元件对于下颌骨模式形成和发育所必需的基因至关重要。有趣的是，在 Gli3 和 Hand2 共同占据的位点进行基序分析揭示了下颌骨特异性、低亲和力、“发散”Gli 结合基序（GBMs）。功能验证表明，这些 GBMs 协同激活了下颌骨模式形成和发育所必需的 Gli 靶基因。总之，这项工作阐明了颅面复合体中Gli 转录活性的一种新的、依赖于序列的机制，这种机制独立于分级的 Hh 信号。

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