Gene Regulatory Strategies that Decode the Duration of NFκB Dynamics Contribute to LPS- versus TNF-Specific Gene Expression
Gene Regulatory Strategies that Decode the Duration of NFκB Dynamics Contribute to LPS- versus TNF-Specific Gene Expression
复制标题
DOI：
10.1016/j.cels.2019.12.004
复制
发表时间：
2020-02-26
期刊：
影响因子：
9.3
通讯作者：
Hoffmann, Alexander
中科院分区：
文献类型：
--
作者：
Sen, Supriya;Cheng, Zhang;Hoffmann, Alexander
病原体衍生的脂多糖（LPS）和细胞因子肿瘤坏死因子（TNF）激活NF κ B B具有不同的持续时间动力学，但免疫应答基因如何解码NF κ B B持续时间以产生刺激特异性表达仍不清楚。在这里，详细的转录组分析的组合和时间控制突变体确定了81个基因，依赖于刺激特异性NF κ B持续时间为他们的刺激特异性。将定量实验与数学建模相结合，我们发现对于某些基因，长的mRNA半衰期允许有效解码，但对于许多基因，这不足以解释数据;相反，我们发现染色质机制，例如非活性和RelA结合增强子状态之间的缓慢转换速率，也可以解码NF κ B B动力学。染色质介导的解码受到作为免疫效应物的基因的青睐（例如，组织重塑剂和T细胞募集剂）而不是免疫调节剂（例如，信号蛋白和单核细胞募集物）。总体而言，我们的研究结果描绘了两个基因调控策略，解码刺激特异性NF κ B动力学和确定不同的生物学功能。
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.