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Gene Regulatory Strategies that Decode the Duration of NF?B Dynamics Contribute to LPS- versus TNF-Specific Gene Expression.


ABSTRACT: Pathogen-derived lipopolysaccharide (LPS) and cytokine tumor necrosis factor (TNF) activate NF?B with distinct duration dynamics, but how immune response genes decode NF?B duration to produce stimulus-specific expression remains unclear. Here, detailed transcriptomic profiling of combinatorial and temporal control mutants identified 81 genes that depend on stimulus-specific NF?B duration for their stimulus-specificity. Combining quantitative experimentation with mathematical modeling, we found that for some genes a long mRNA half-life allowed effective decoding, but for many genes this was insufficient to account for the data; instead, we found that chromatin mechanisms, such as a slow transition rate between inactive and RelA-bound enhancer states, could also decode NF?B dynamics. Chromatin-mediated decoding is favored by genes acting as immune effectors (e.g., tissue remodelers and T cell recruiters) rather than immune regulators (e.g., signaling proteins and monocyte recruiters). Overall, our results delineate two gene regulatory strategies that decode stimulus-specific NF?B dynamics and determine distinct biological functions.

SUBMITTER: Sen S 

PROVIDER: S-EPMC7047529 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Gene Regulatory Strategies that Decode the Duration of NFκB Dynamics Contribute to LPS- versus TNF-Specific Gene Expression.

Sen Supriya S   Cheng Zhang Z   Sheu Katherine M KM   Chen Yu Hsin YH   Hoffmann Alexander A  

Cell systems 20200122 2


Pathogen-derived lipopolysaccharide (LPS) and cytokine tumor necrosis factor (TNF) activate NFκB with distinct duration dynamics, but how immune response genes decode NFκB duration to produce stimulus-specific expression remains unclear. Here, detailed transcriptomic profiling of combinatorial and temporal control mutants identified 81 genes that depend on stimulus-specific NFκB duration for their stimulus-specificity. Combining quantitative experimentation with mathematical modeling, we found t  ...[more]

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