期刊
CELL SYSTEMS
卷 10, 期 2, 页码 169-+出版社
CELL PRESS
DOI: 10.1016/j.cels.2019.12.004
关键词
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资金
- NIH [GM117134, AI127864, AI132835]
- UCLA Medical Scientist Training Program [NIH NIGMS T32 GM008042]
Pathogen-derived lipopolysaccharide (LPS) and cytokine tumor necrosis factor (TNF) activate NF kappa B with distinct duration dynamics, but how immune response genes decode NF kappa 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 kappa 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 kappa 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 kappa B dynamics and determine distinct biological functions.
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