Rodrigo Guillermo, Bajić Djordje, Elola Ignacio, Poyatos Juan F
Instituto de Biología Molecular y Celular de Plantas, CSIC-UPV, 46022 Valencia, Spain.
Logic of Genomic Systems Laboratory, CNB-CSIC, 28049 Madrid, Spain.
NPJ Syst Biol Appl. 2017 Oct 6;3:30. doi: 10.1038/s41540-017-0031-2. eCollection 2017.
Many essential bacterial responses present complex transcriptional regulation of gene expression. To what extent can the study of these responses substantiate the logic of their regulation? Here, we show how the input function of the genes constituting the response, i.e., the information of how their transcription rates change as function of the signals acting on the regulators, can serve as a quantitative tool to deconstruct the corresponding regulatory logic. To demonstrate this approach, we consider the multiple antibiotic resistance () response in . By characterizing the input function of its representative genes in wild-type and mutant bacteria, we recognize a dual autoregulation motif as main determinant of the response, which is further adjusted by the interplay with other regulators. We show that basic attributes, like its reaction to a wide range of stress or its moderate expression change, are associated with a strong negative autoregulation, while others, like the buffering of metabolic signals or the lack of memory to previous stress, are related to a weak positive autoregulation. With a mathematical model of the input functions, we identify some constraints fixing the molecular attributes of the regulators, and also notice the relevance of the bicystronic architecture harboring the dual autoregulation that is unique in . The input function emerges then as a tool to disentangle the rationale behind most of the attributes defining the phenotype. Overall, the present study supports the value of characterizing input functions to deconstruct the complexity of regulatory architectures in prokaryotic and eukaryotic systems.
许多重要的细菌反应呈现出基因表达的复杂转录调控。对这些反应的研究在多大程度上能够证实其调控逻辑？在这里，我们展示了构成该反应的基因的输入函数，即它们的转录速率如何随作用于调节因子的信号而变化的信息，如何能够作为一种定量工具来解构相应的调控逻辑。为了证明这种方法，我们考虑了大肠杆菌中的多重抗生素耐药性（Mar）反应。通过表征野生型和突变型细菌中其代表性基因的输入函数，我们识别出一种双重自动调节基序是该反应的主要决定因素，它通过与其他调节因子的相互作用进一步得到调整。我们表明，其对广泛应激的反应或适度的表达变化等基本属性与强烈的负向自动调节相关，而其他属性，如代谢信号的缓冲或对先前应激缺乏记忆，则与微弱的正向自动调节有关。通过输入函数的数学模型，我们确定了一些固定调节因子分子属性的限制条件，并且还注意到具有双重自动调节的双顺反子结构在大肠杆菌中的独特相关性。然后，输入函数成为一种工具，用于厘清定义Mar表型的大多数属性背后的原理。总体而言，本研究支持表征输入函数对于解构原核生物和真核生物系统中调控结构复杂性的价值。
