Mapping the Shh long-range regulatory domain.
Mapping the Shh long-range regulatory domain.
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DOI：
10.1242/dev.108480
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发表时间：
2014-10
期刊：
影响因子：
--
通讯作者：
Lettice LA
中科院分区：
文献类型：
--
作者：
Anderson E;Devenney PS;Hill RE;Lettice LA
由长距离增强子控制的协调基因表达是由涉及转录因子和控制机制层的DNA调控序列精心策划的。 Shh 基因和完善的调节子是基因组组成的一个例子，其中增强子位于大沙漠中，延伸到邻近基因以控制表达的时空模式。利用睡美人转座子的局部跳跃活性，将 lacZ 报告基因分散在整个 Shh 区域，以系统地绘制负责表达活性的基因组特征。我们发现增强子活性保留在与 Hi-C 定义的拓扑相关域 (TAD) 相对应的基因组区域内。这个大约 900 kb 的结构域在其长度上处于开放构象，并且通常对所有 Shh 增强子敏感。与远端增强子类似，Shh 第二个内含子内的增强子会激活数百个碱基外的报告基因，这表明近端和远端增强子都有能力调查 Shh 拓扑结构域以识别潜在的启动子。位于 Shh 结构域内的广泛表达的 Rnf32 基因通过一个可能在其他位于大调控结构域中的管家基因中常见的过程来逃避增强子活性。最后，Shh TAD 的边界并不代表增强子活性的绝对表达极限，因为在这些结构域边缘的许多基因组位置处表达活性逐步丧失。
Coordinated gene expression controlled by long-distance enhancers is orchestrated by DNA regulatory sequences involving transcription factors and layers of control mechanisms. The Shh gene and well-established regulators are an example of genomic composition in which enhancers reside in a large desert extending into neighbouring genes to control the spatiotemporal pattern of expression. Exploiting the local hopping activity of the Sleeping Beauty transposon, the lacZ reporter gene was dispersed throughout the Shh region to systematically map the genomic features responsible for expression activity. We found that enhancer activities are retained inside a genomic region that corresponds to the topological associated domain (TAD) defined by Hi-C. This domain of approximately 900 kb is in an open conformation over its length and is generally susceptible to all Shh enhancers. Similar to the distal enhancers, an enhancer residing within the Shh second intron activates the reporter gene located at distances of hundreds of kilobases away, suggesting that both proximal and distal enhancers have the capacity to survey the Shh topological domain to recognise potential promoters. The widely expressed Rnf32 gene lying within the Shh domain evades enhancer activities by a process that may be common among other housekeeping genes that reside in large regulatory domains. Finally, the boundaries of the Shh TAD do not represent the absolute expression limits of enhancer activity, as expression activity is lost stepwise at a number of genomic positions at the verges of these domains.
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