Exploring the mono-/bistability range of positively autoregulated signaling systems in the presence of competing transcription factor binding sites.
Exploring the mono-/bistability range of positively autoregulated signaling systems in the presence of competing transcription factor binding sites.
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DOI：
10.1371/journal.pcbi.1010738
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发表时间：
2022-11
影响因子：
4.3
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中科院分区：
文献类型：
--
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Binding of transcription factor (TF) proteins to regulatory DNA sites is key to accurate control of gene expression in response to environmental stimuli. Theoretical modeling of transcription regulation is often focused on a limited set of genes of interest, while binding of the TF to other genomic sites is seldom considered. The total number of TF binding sites (TFBSs) affects the availability of TF protein molecules and sequestration of a TF by TFBSs can promote bistability. For many signaling systems where a graded response is desirable for continuous control over the input range, biochemical parameters of the regulatory proteins need be tuned to avoid bistability. Here we analyze the mono-/bistable parameter range for positively autoregulated two-component systems (TCSs) in the presence of different numbers of competing TFBSs. TCS signaling, one of the major bacterial signaling strategies, couples signal perception with output responses via protein phosphorylation. For bistability, competition for TF proteins by TFBSs lowers the requirement for high fold change of the autoregulated transcription but demands high phosphorylation activities of TCS proteins. We show that bistability can be avoided with a low phosphorylation capacity of TCSs, a high TF affinity for the autoregulated promoter or a low fold change in signaling protein levels upon induction. These may represent general design rules for TCSs to ensure uniform graded responses. Examining the mono-/bistability parameter range allows qualitative prediction of steady-state responses, which are experimentally validated in the E. coli CusRS system. Cell survival in an ever-changing environment depends on appropriate responses to stimuli of different strengths. Bistability, i.e., two different stable states in responses to otherwise identical environments, can be beneficial in some systems but may need to be avoided by many signaling systems. Promoting or preventing bistable responses requires specific architectures of gene regulatory networks as well as proper abundance and activities for the network building blocks. Here we use a mathematical model to study how the requirement for bistable or monostable responses places constraints on biochemical properties of autoregulated bacterial signaling systems. A particular focus is on how the relative abundance of transcription factor proteins to the number of their DNA target sites constrains the system design because competition for the limited TF protein molecules by DNA sites can promote bistability. We find that a strong binding affinity to the autoregulated TF promoter and low phosphorylation activities are preferred for monostability. We used an E. coli signaling system as an example and experimentally validated predictions of the model. Our results can help rationalize the regulatory features observed in naturally occurring systems as well as inform engineering of novel biological circuits for diverse signaling tasks.
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