Environment-specific combinatorial cis-regulation in synthetic promoters.
Environment-specific combinatorial cis-regulation in synthetic promoters.
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DOI：
10.1038/msb.2009.1
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发表时间：
2009
影响因子：
9.9
通讯作者：
中科院分区：
文献类型：
--
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当细胞环境发生变化时，通常会发生大规模的转录反应。这些反应的敏感性和特异性在很大程度上是由位于基因启动子和邻近控制区的顺式调控元件的组合控制的。在这里，我们提出了一项研究，旨在准确地模拟顺式调控元件的组合及其在不同环境中驱动的表达水平之间的关系。我们在酵母中构建了四个由转录因子结合位点组合组成的合成启动子文库，并检测了它们在四种不同环境下的表达。启动子序列与其对应的四个表达水平相关的热力学模型通过不同的条件解释了每个文库中至少56%的表达差异。对这些模型的分析表明，大部分受调控的基因表达可以通过序列特异性转录因子有效浓度的变化来解释，并且我们表明，在大多数情况下，相应的转录因子以热力学模型预测的模式表达。我们的分析揭示了两个结合位点在不同的环境条件下从激活因子转换为抑制因子。在这两种情况下，这种转换都不是单个转录因子改变调控模式的结果，而很可能是由于结合到同一位点的多个因子之间的竞争。我们的分析表明，这种调节模式允许表达随着转录因子浓度的变化而发生大而陡的变化。我们的研究结果表明，基因表达的许多复杂变化可以通过转录因子有效浓度的简单变化来准确解释。
When a cell's environment changes, a large transcriptional response often takes place. The exquisite sensitivity and specificity of these responses are controlled in large part by the combinations of cis-regulatory elements that reside in gene promoters and adjacent control regions. Here, we present a study aimed at accurately modeling the relationship between combinations of cis-regulatory elements and the expression levels they drive in different environments. We constructed four libraries of synthetic promoters in yeast, consisting of combinations of transcription factor binding sites and assayed their expression in four different environments. Thermodynamic models relating promoter sequences to their corresponding four expression levels explained at least 56% of the variation in expression in each library through the different conditions. Analyses of these models suggested that a large fraction of regulated gene expression is explained by changes in the effective concentration of sequence-specific transcription factors, and we show that in most cases, the corresponding transcription factors are expressed in a pattern that is predicted by the thermodynamic models. Our analysis uncovered two binding sites that switch from activators to repressors in different environmental conditions. In both the cases, the switch was not the result of a single transcription factor changing regulatory modes, but most likely due to competition between multiple factors binding to the same site. Our analysis suggests that this mode of regulation allows for large and steep changes in expression in response to changing transcription factor concentrations. Our results demonstrate that many complex changes in gene expression are accurately explained by simple changes in the effective concentrations of transcription factors.
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