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。Fe是许多酶的辅因子或结构组分，这些酶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。在低铁条件下生长期间，细菌在其环境中分泌称为铁载体（肠杆菌素）的分子，这使得铁在运输到细胞内之前溶解。几十年来，大肠杆菌铁载体的合成被认为是在转录水平上由铁响应转录抑制子Fur完全调控的。然而，在我们的研究过程中，我们观察到小RNA RyhB是铁载体正常产生所必需的。首先，RyhB直接抑制cysE的翻译，cysE编码丝氨酸乙酰转移酶，其使用丝氨酸作为半胱氨酸生物合成的底物。通过RyhB减少CysE活性允许丝氨酸用作肠杆菌素合成的结构单元。其次，我们发现RyhB是一个强大的细胞内Fe稳态的关键，这是参与肠杆菌素生物合成的一组重要基因的正常表达所必需的。除此之外，我们的初步数据表明，翻译机制成为缺乏铁稳态的细胞。这些惊人的结果强调了一个事实，即尽管经过几十年的深入研究，我们仍然不了解铁的许多关键生理作用。基于我们的研究，我们开创了一个富有成效的方法在调查铁，这揭示了许多未知的机制。我们想了解这些新的机制，这就是为什么我的研究计划旨在整合sRNA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）基因表达的铁依赖性调节。

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.