Computational reconstruction of iron- and manganese-responsive transcriptional networks in alpha-proteobacteria.
Computational reconstruction of iron- and manganese-responsive transcriptional networks in alpha-proteobacteria.
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α-变形菌中铁和锰响应转录网络的计算重建。
DOI：
10.1371/journal.pcbi.0020163
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发表时间：
2006-12-15
影响因子：
4.3
通讯作者：
Johnston, Andrew W. B.
中科院分区：
文献类型：
--
作者：
Rodionov, Dmitry A.;Gelfand, Mikhail S.;Todd, Jonathan D.;Curson, Andrew R. J.;Johnston, Andrew W. B.
我们使用比较基因组学来研究在α-蛋白细菌中与铁和锰稳态有关的基因的调控区域中保守的DNA结合基序的分布。结合其他计算方法，这使我们能够重建30多个物种中具有可用基因组序列的金属调控网络。我们在不同基因的调控区域中发现了几类顺式作用的调控基序(irr盒或ICs、Rira盒、Iron-Rhodo盒、Fur-α盒、Mur-box或MRS、MntR-box和Iscr-box)，这些基因涉及铁和锰的吸收、Fe-S和血红素的生物合成、铁的储存和利用。尽管在选定的阿尔法蛋白细菌谱系中铁调节蛋白的性质不同，但总体调节网络与许多实验观察结果一致并得到证实。这项研究扩大了涉及铁稳态的基因范围，并证明了铁反应调节系统之间存在相当大的相互联系。对调控系统的详细比较和系统发育分析使我们能够提出一种关于α-蛋白细菌中铁和锰调控子可能进化的理论。主要的进化事件可能发生在根瘤目和红杆菌目的共同祖先中，其中Fur蛋白转换为调节锰转运蛋白(因此Fur成为Mur)。在这些谱系中，全球铁稳态的作用由RIRA和IRR承担，这两个转录调节因子通过感知金属可获得性的生理后果而不是其本身的浓度来发挥作用，从而提供了更灵活的调节。数百个完整基因组的可获得性使人们能够使用比较基因组学来描述关键的代谢过程和调控基因网络。基因组上下文分析和基因组间转录因子结合位点的比较为功能基因注释提供了一种强有力的方法。转录调控网络的重建允许更好地理解细胞过程，这可以通过直接实验来证实。细菌体内的铁平衡是通过调节各种铁摄取转运蛋白、铁储存铁蛋白和含铁酶来实现的。在高浓度下，铁对细胞是有毒的，所以对铁的稳态保持严格的控制，主要是在转录水平上由铁反应调节器来控制。尽管它们具有普遍的重要性，但大多数细菌物种中的铁调节网络还没有被很好地理解。在这项研究中，Rodionov和他的同事应用比较基因组学方法来描述由参与铁稳态的基因在变形杆菌的阿尔法亚类中形成的调控网络，这种细菌的生活方式非常多样化。这些网络由一组不同的DNA基序(或调控信号)介导，这些DNA基序(或调控信号)发生在5‘基因区，涉及至少六种不同的金属反应调节因子。这项研究再次展示了比较基因组学在分析复杂的调控网络及其进化方面的力量。
We used comparative genomics to investigate the distribution of conserved DNA-binding motifs in the regulatory regions of genes involved in iron and manganese homeostasis in alpha-proteobacteria. Combined with other computational approaches, this allowed us to reconstruct the metal regulatory network in more than three dozen species with available genome sequences. We identified several classes of cis-acting regulatory DNA motifs (Irr-boxes or ICEs, RirA-boxes, Iron-Rhodo-boxes, Fur-alpha-boxes, Mur-box or MRS, MntR-box, and IscR-boxes) in regulatory regions of various genes involved in iron and manganese uptake, Fe-S and heme biosynthesis, iron storage, and usage. Despite the different nature of the iron regulons in selected lineages of alpha-proteobacteria, the overall regulatory network is consistent with, and confirmed by, many experimental observations. This study expands the range of genes involved in iron homeostasis and demonstrates considerable interconnection between iron-responsive regulatory systems. The detailed comparative and phylogenetic analyses of the regulatory systems allowed us to propose a theory about the possible evolution of Fe and Mn regulons in alpha-proteobacteria. The main evolutionary event likely occurred in the common ancestor of the Rhizobiales and Rhodobacterales, where the Fur protein switched to regulating manganese transporters (and hence Fur had become Mur). In these lineages, the role of global iron homeostasis was taken by RirA and Irr, two transcriptional regulators that act by sensing the physiological consequence of the metal availability rather than its concentration per se, and thus provide for more flexible regulation. The availability of hundreds of complete genomes allows one to use comparative genomics to describe key metabolic processes and regulatory gene networks. Genome context analyses and comparisons of transcription factor binding sites between genomes offer a powerful approach for functional gene annotation. Reconstruction of transcriptional regulatory networks allows for better understanding of cellular processes, which can be substantiated by direct experimentation. Iron homeostasis in bacteria is conferred by the regulation of various iron uptake transporters, iron storage ferritins, and iron-containing enzymes. In high concentrations, iron is poisonous for the cell, so strict control of iron homeostasis is maintained, mostly at the level of transcription by iron-responsive regulators. Despite their general importance, iron regulatory networks in most bacterial species are not well-understood. In this study, Rodionov and colleagues applied comparative genomic approaches to describe the regulatory network formed by genes involved in iron homeostasis in the alpha subclass of proteobacteria, which have extremely versatile lifestyles. These networks are mediated by a set of various DNA motifs (or regulatory signals) that occur in 5′ gene regions and involve at least six different metal-responsive regulators. This study once again shows the power of comparative genomics in the analysis of complex regulatory networks and their evolution.
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