Enhancer architecture sensitizes cell specific responses to Notch gene dose via a bind and discard mechanism
Enhancer architecture sensitizes cell specific responses to Notch gene dose via a bind and discard mechanism
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DOI：
10.7554/elife.53659
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发表时间：
2020-04-16
期刊：
影响因子：
7.7
通讯作者：
Gebelein, Brian
中科院分区：
文献类型：
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作者：
Yi Kuang;Golan, Ohad;Gebelein, Brian
Notch通路单倍性不足可导致严重的发育综合征，具有高度可变的突变率。目前，我们对基因剂量引起的表型变异性的机理认识有限。在这里，我们意外地发现，插入一个增强子含有先锋转录因子位点耦合到Notch二聚体位点可以诱导一个子集的Notch单倍不足的表型在果蝇与野生型Notch基因剂量。使用果蝇遗传学，我们表明，这种增强子诱导Notch表型的Cdk8依赖，转录独立的方式。我们进一步将数学建模与定量性状和表达分析相结合，建立了一个模型，该模型描述了Notch信号产生与降解的变化如何不同地影响需要长信号持续时间与短信号持续时间的细胞结果。总之，这些发现支持了一种“结合和丢弃”机制，其中具有特异性结合位点的增强子促进快速Cdk8依赖性Notch周转，从而减少其他位点的Notch依赖性转录，并使组织对基于信号持续时间的基因剂量敏感。
Notch pathway haploinsufficiency can cause severe developmental syndromes with highly variable penetrance. Currently, we have a limited mechanistic understanding of phenotype variability due to gene dosage. Here, we unexpectedly found that inserting an enhancer containing pioneer transcription factor sites coupled to Notch dimer sites can induce a subset of Notch haploinsufficiency phenotypes in Drosophila with wild type Notch gene dose. Using Drosophila genetics, we show that this enhancer induces Notch phenotypes in a Cdk8-dependent, transcription-independent manner. We further combined mathematical modeling with quantitative trait and expression analysis to build a model that describes how changes in Notch signal production versus degradation differentially impact cellular outcomes that require long versus short signal duration. Altogether, these findings support a 'bind and discard' mechanism in which enhancers with specific binding sites promote rapid Cdk8-dependent Notch turnover, and thereby reduce Notch-dependent transcription at other loci and sensitize tissues to gene dose based upon signal duration.