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1.
Elife ; 102021 03 08.
Article in English | MEDLINE | ID: mdl-33683203

ABSTRACT

Gene expression levels are influenced by multiple coexisting molecular mechanisms. Some of these interactions such as those of transcription factors and promoters have been studied extensively. However, predicting phenotypes of gene regulatory networks (GRNs) remains a major challenge. Here, we use a well-defined synthetic GRN to study in Escherichia coli how network phenotypes depend on local genetic context, i.e. the genetic neighborhood of a transcription factor and its relative position. We show that one GRN with fixed topology can display not only quantitatively but also qualitatively different phenotypes, depending solely on the local genetic context of its components. Transcriptional read-through is the main molecular mechanism that places one transcriptional unit (TU) within two separate regulons without the need for complex regulatory sequences. We propose that relative order of individual TUs, with its potential for combinatorial complexity, plays an important role in shaping phenotypes of GRNs.


Subject(s)
Gene Expression Regulation/genetics , Gene Regulatory Networks/genetics , Models, Genetic , Transcription Factors , Computational Biology , Escherichia coli/genetics , Escherichia coli Proteins/genetics , Genes, Bacterial/genetics , Transcription Factors/genetics , Transcription Factors/metabolism
2.
PLoS Comput Biol ; 17(1): e1008529, 2021 01.
Article in English | MEDLINE | ID: mdl-33411759

ABSTRACT

Phenomenological relations such as Ohm's or Fourier's law have a venerable history in physics but are still scarce in biology. This situation restrains predictive theory. Here, we build on bacterial "growth laws," which capture physiological feedback between translation and cell growth, to construct a minimal biophysical model for the combined action of ribosome-targeting antibiotics. Our model predicts drug interactions like antagonism or synergy solely from responses to individual drugs. We provide analytical results for limiting cases, which agree well with numerical results. We systematically refine the model by including direct physical interactions of different antibiotics on the ribosome. In a limiting case, our model provides a mechanistic underpinning for recent predictions of higher-order interactions that were derived using entropy maximization. We further refine the model to include the effects of antibiotics that mimic starvation and the presence of resistance genes. We describe the impact of a starvation-mimicking antibiotic on drug interactions analytically and verify it experimentally. Our extended model suggests a change in the type of drug interaction that depends on the strength of resistance, which challenges established rescaling paradigms. We experimentally show that the presence of unregulated resistance genes can lead to altered drug interaction, which agrees with the prediction of the model. While minimal, the model is readily adaptable and opens the door to predicting interactions of second and higher-order in a broad range of biological systems.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria , Drug Interactions/physiology , Models, Biological , Bacteria/drug effects , Bacteria/genetics , Biophysical Phenomena , Drug Resistance, Bacterial/drug effects , Drug Resistance, Bacterial/genetics , Drug Resistance, Bacterial/physiology , Feedback, Physiological/drug effects , Ribosomes/drug effects
3.
Nat Commun ; 11(1): 4013, 2020 08 11.
Article in English | MEDLINE | ID: mdl-32782250

ABSTRACT

Antibiotics that interfere with translation, when combined, interact in diverse and difficult-to-predict ways. Here, we explain these interactions by "translation bottlenecks": points in the translation cycle where antibiotics block ribosomal progression. To elucidate the underlying mechanisms of drug interactions between translation inhibitors, we generate translation bottlenecks genetically using inducible control of translation factors that regulate well-defined translation cycle steps. These perturbations accurately mimic antibiotic action and drug interactions, supporting that the interplay of different translation bottlenecks causes these interactions. We further show that growth laws, combined with drug uptake and binding kinetics, enable the direct prediction of a large fraction of observed interactions, yet fail to predict suppression. However, varying two translation bottlenecks simultaneously supports that dense traffic of ribosomes and competition for translation factors account for the previously unexplained suppression. These results highlight the importance of "continuous epistasis" in bacterial physiology.


Subject(s)
Anti-Bacterial Agents/pharmacology , Models, Theoretical , Protein Biosynthesis/drug effects , Protein Synthesis Inhibitors/pharmacology , Drug Interactions , Epistasis, Genetic , Escherichia coli/drug effects , Escherichia coli/physiology , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , Protein Biosynthesis/physiology , Ribosomal Proteins/genetics , Ribosomal Proteins/metabolism , Ribosomes/drug effects , Ribosomes/metabolism
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