National Key Laboratory of Agricultural Microbiology, Center for Proteomics Research, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
J Proteome Res. 2012 Sep 7;11(9):4682-92. doi: 10.1021/pr3006233. Epub 2012 Aug 10.
Transcription regulation translates static genome information to dynamic cell behaviors, making it central to understand how cells interact with and adapt to their environment. However, only a limited number of transcription regulators and their target genes have been identified in the pathogen Mycobacterium tuberculosis , which has greatly impeded our understanding of its pathogenesis and virulence. In this study, we constructed a genome-wide transcription regulatory network of M. tuberculosis H37Rv using a high-throughput bacterial one-hybrid technique. A transcription factor skeleton network was derived on the basis of the identification of more than 5400 protein-DNA interactions. Our findings further highlight the regulatory mechanism of the mammalian cell entry 1 (mce1) module, which includes mce1R and the mce1 operon. Mce1R was linked to global negative regulation of cell growth, but was found to be positively regulated by the dormancy response regulator DevR. Expression of the mce1 operon was shown to be negatively regulated by the virulence regulator PhoP. These findings provide important new insights into the molecular mechanisms of several mce1 module-related hypervirulence phenotypes of the pathogen. Furthermore, a model of mce1 module-centered signal circuit for dormancy regulation in M. tuberculosis is proposed and discussed.
转录调控将静态的基因组信息转化为动态的细胞行为，使其成为理解细胞如何与环境相互作用和适应环境的核心。然而，在病原体结核分枝杆菌中，只有有限数量的转录调控因子及其靶基因被鉴定出来，这极大地阻碍了我们对其发病机制和毒力的理解。在这项研究中，我们使用高通量细菌单杂交技术构建了结核分枝杆菌 H37Rv 的全基因组转录调控网络。在鉴定了超过 5400 个蛋白-DNA 相互作用的基础上，得出了转录因子骨架网络。我们的研究结果进一步强调了哺乳动物细胞进入 1（mce1）模块的调控机制，该模块包括 mce1R 和 mce1 操纵子。mce1R 与细胞生长的全局负调控有关，但被发现受到休眠反应调节剂 DevR 的正调控。mce1 操纵子的表达被毒力调节因子 PhoP 负调控。这些发现为该病原体的几个 mce1 模块相关高毒力表型的分子机制提供了重要的新见解。此外，还提出并讨论了一个以 mce1 模块为中心的结核分枝杆菌休眠调节信号回路模型。
