Sonnenschein Nikolaus, Geertz Marcel, Muskhelishvili Georgi, Hütt Marc-Thorsten
Jacobs University Bremen, 28759 Bremen, Germany.
BMC Syst Biol. 2011 Mar 15;5:40. doi: 10.1186/1752-0509-5-40.
The 3D structure of the chromosome of the model organism Escherichia coli is one key component of its gene regulatory machinery. This type of regulation mediated by topological transitions of the chromosomal DNA can be thought of as an analog control, complementing the digital control, i.e. the network of regulation mediated by dedicated transcription factors. It is known that alterations in the superhelical density of chromosomal DNA lead to a rich pattern of differential expressed genes. Using a network approach, we analyze these expression changes for wild type E. coli and mutants lacking nucleoid associated proteins (NAPs) from a metabolic and transcriptional regulatory network perspective.
We find a significantly higher correspondence between gene expression and metabolism for the wild type expression changes compared to mutants in NAPs, indicating that supercoiling induces meaningful metabolic adjustments. As soon as the underlying regulatory machinery is impeded (as for the NAP mutants), this coherence between expression changes and the metabolic network is substantially reduced. This effect is even more pronounced, when we compute a wild type metabolic flux distribution using flux balance analysis and restrict our analysis to active reactions. Furthermore, we are able to show that the regulatory control exhibited by DNA supercoiling is not mediated by the transcriptional regulatory network (TRN), as the consistency of the expression changes with the TRN logic of activation and suppression is strongly reduced in the wild type in comparison to the mutants.
So far, the rich patterns of gene expression changes induced by alterations of the superhelical density of chromosomal DNA have been difficult to interpret. Here we characterize the effective networks formed by supercoiling-induced gene expression changes mapped onto reconstructions of E. coli's metabolic and transcriptional regulatory network. Our results show that DNA supercoiling coordinates gene expression with metabolism. Furthermore, this control is acting directly because we can exclude the potential role of the TRN as a mediator.
模式生物大肠杆菌染色体的三维结构是其基因调控机制的一个关键组成部分。这种由染色体DNA拓扑转变介导的调控类型可被视为一种模拟控制，它补充了数字控制，即由专用转录因子介导的调控网络。已知染色体DNA超螺旋密度的改变会导致差异表达基因的丰富模式。我们使用网络方法，从代谢和转录调控网络的角度分析野生型大肠杆菌和缺乏类核相关蛋白（NAPs）的突变体的这些表达变化。
我们发现，与NAPs突变体相比，野生型表达变化中基因表达与代谢之间的对应性显著更高，这表明超螺旋诱导了有意义的代谢调整。一旦潜在的调控机制受到阻碍（如NAP突变体的情况），表达变化与代谢网络之间的这种一致性就会大幅降低。当我们使用通量平衡分析计算野生型代谢通量分布并将分析限制在活跃反应时，这种效应更加明显。此外，我们能够表明，DNA超螺旋所展现的调控控制并非由转录调控网络（TRN）介导，因为与突变体相比，野生型中表达变化与TRN激活和抑制逻辑的一致性大幅降低。
到目前为止，由染色体DNA超螺旋密度改变诱导的丰富基因表达变化模式一直难以解释。在这里，我们表征了由映射到大肠杆菌代谢和转录调控网络重建上的超螺旋诱导基因表达变化所形成的有效网络。我们的结果表明，DNA超螺旋将基因表达与代谢协调起来。此外，这种控制是直接起作用的，因为我们可以排除TRN作为介导者的潜在作用。
