Mechanisms of gene regulation by iron

铁（Fe）是几乎所有原核生物和真核生物最重要的金属。铁是许多酶的辅助因子或结构成分，参与代谢的关键步骤，如呼吸，TCA循环，RNA修饰，DNA合成和基因调控。在低铁条件下生长的过程中，细菌在其环境中分泌一种叫做铁载体（肠杆菌）的分子，这种分子在铁被运输到细胞内之前使铁溶解。几十年来，大肠杆菌对铁载体的合成被认为在转录水平上完全受铁响应转录抑制因子Fur的调控。然而，在我们的研究过程中，我们观察到小RNA RyhB对铁载体的正常产生至关重要。首先，RyhB直接抑制cysE的翻译，cysE编码一种丝氨酸乙酰转移酶，该酶利用丝氨酸作为半胱氨酸生物合成的底物。通过RyhB降低CysE活性允许丝氨酸用作肠杆菌蛋白合成的构建块。其次，我们发现RyhB是细胞内铁稳态的关键，这是参与肠杆菌蛋白生物合成的一组重要基因正常表达所必需的。除此之外，我们的初步数据表明，在没有铁稳态的细胞中，翻译机制会出现缺陷。这些惊人的结果强调了一个事实，即尽管经过了几十年的深入研究，我们仍然不了解铁的许多关键生理作用。基于我们的研究，我们开创了一种富有成效的方法来研究铁，揭示了许多未表征的机制。我们想要了解这些新的机制，这就是为什么我的研究项目旨在整合sRNA的功能，代谢和基因表达，所有这些都依赖于铁。在这个项目中，我们的长期目标是表征铁在基因调控和代谢中的重要作用。该计划有两个短期目标：表征(1)rna调节的代谢途径；探索(2)铁对基因表达的依赖性调控。

Iron (Fe) is the most important metal for nearly all prokaryotes and eukaryotes. Fe is a cofactor or structural component of numerous enzymes that participate in key steps of the metabolism such as respiration, TCA cycle, RNA modification, DNA synthesis, and gene regulation. During growth under low-Fe conditions, bacteria secrete in their environment molecules called siderophores (enterobactin), which makes the Fe soluble before it is transported inside the cell. For decades, the synthesis of siderophores by Escherichia coli was considered to be fully regulated at the transcriptional level by the Fe-responsive transcriptional repressor Fur. However, during the course of our study, we observed that the small RNA RyhB was essential for normal production of siderophore. First, RyhB directly represses the translation of cysE, which encodes a serine acetyltransferase that uses serine as a substrate for cysteine biosynthesis. Reduction of CysE activity by RyhB allows serine to be used as building blocks for enterobactin synthesis. Second, we found that RyhB is key to a robust intracellular Fe homeostasis, which is required for normal expression of an important group of genes involved in enterobactin biosynthesis. Beyond this, our preliminary data indicate that the translational machinery becomes deficient in cells without Fe homeostasis. These striking results underline the fact that, despite several decades of intensive studies, we still do not understand many key physiological roles of Fe. Based on our study, we have pioneered a fruitful approach in the investigation of Fe, which has revealed many uncharacterized mechanisms. We want to understand these novel mechanisms and this is why my research program aims at integrating sRNA functions, metabolism, and gene expression, all of them Fe-dependent. In this program, our long-term goal is to characterize the essential role of Fe in gene regulation and metabolism. This program has two short-term goals: to characterize (1) RNA-modulated metabolic routes; and to explore (2) Fe-dependent regulation of gene expression.