The Conserved Sonic Hedgehog Limb Enhancer Consists of Discrete Functional Elements that Regulate Precise Spatial Expression.
The Conserved Sonic Hedgehog Limb Enhancer Consists of Discrete Functional Elements that Regulate Precise Spatial Expression.
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DOI：
10.1016/j.celrep.2017.07.037
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发表时间：
2017-08-08
期刊：
影响因子：
8.8
通讯作者：
Hill RE
中科院分区：
文献类型：
--
作者：
Lettice LA;Devenney P;De Angelis C;Hill RE
肢体芽中sonic hedgehog （Shh）的表达受一种称为极化活动调控序列（zone of polarization activity regulatory sequence， ZRS）的增强子调控，该增强子在进化过程中属于一组古老的高度保守的顺式调控子，存在于所有脊椎动物中。在这里，我们检测了小鼠的内源性ZRS，使用基因组编辑来建立增强子组成与胚胎表型之间的关系。我们发现增强子的活动是不同活动域的巩固。Shh表达的空间限制是由一个离散的抑制因子模块介导的，而基因表达水平是由包含不同数量的HOXD结合位点的大重叠结构域控制的。HOXD结合位点的数量逐渐调节表达水平。大量的保守序列是可有可无的，表明存在序列冗余。我们提出了一个增强子活动的集体模型，其中功能是离散表达活动和驱动鲁棒表达的冗余组件的集成。古老的脊椎动物增强子ZRS显示出序列可塑性，离散的调控活动被分配到增强子中的特定位点，HOXD结合位点的数量决定了Shh表达的水平，稳健的表达是调控和冗余信息的集合，Lettice等人通过使用基因组编辑分析内源性序列，研究了高度保守的肢体特异性增强子ZRS的组成。对结果表型的分析可以深入了解增强子的复杂组成，它整合了离散的表达活动和冗余元素，以驱动精确的时空基因表达。
Expression of sonic hedgehog (Shh) in the limb bud is regulated by an enhancer called the zone of polarizing activity regulatory sequence (ZRS), which, in evolution, belongs to an ancient group of highly conserved cis regulators found in all classes of vertebrates. Here, we examined the endogenous ZRS in mice, using genome editing to establish the relationship between enhancer composition and embryonic phenotype. We show that enhancer activity is a consolidation of distinct activity domains. Spatial restriction of Shh expression is mediated by a discrete repressor module, whereas levels of gene expression are controlled by large overlapping domains containing varying numbers of HOXD binding sites. The number of HOXD binding sites regulates expression levels incrementally. Substantial portions of conserved sequence are dispensable, indicating the presence of sequence redundancy. We propose a collective model for enhancer activity in which function is an integration of discrete expression activities and redundant components that drive robust expression. The ancient vertebrate enhancer, the ZRS, shows sequence plasticity Discrete regulatory activities are assigned to specific sites in the enhancer The number of HOXD binding sites determines the level of Shh expression Robust expression is a collective of regulatory and redundant information Lettice et al. examine the composition of a highly conserved limb-specific enhancer, the ZRS, by dissecting the endogenous sequence using genome editing. Analysis of the resulting phenotype gives insights into the complex composition of the enhancer, which integrates discrete expression activities and redundant elements to drive accurate spatiotemporal gene expression.
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