Dissecting the Regulatory Strategies of NF-κB ReIA Target Genes in the Inflammatory Response Reveals Differential Transactivation Logics
Dissecting the Regulatory Strategies of NF-κB ReIA Target Genes in the Inflammatory Response Reveals Differential Transactivation Logics
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DOI：
10.1016/j.celrep.2020.01.108
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发表时间：
2020-02-25
期刊：
影响因子：
8.8
通讯作者：
Hoffmann, Alexander
中科院分区：
文献类型：
--
作者：
Ngo, Kim A.;Kishimoto, Kensei;Hoffmann, Alexander
核因子κ B（NF-κ B）RelA是炎症反应基因的有效转录激活因子。我们通过整合物理（染色质免疫沉淀测序[ChIP-seq]）和功能（敲除中的RNA测序[RNA-seq]）数据集，严格定义了一系列直接RelA靶基因。然后，我们通过在原代细胞遗传互补测定中测试RelA变体来剖析每个基因的调控策略。所有内源性靶基因都需要RelA来进行DNA碱基特异性接触，并且没有一个是单独通过DNA结合结构域激活的。然而，内源性靶基因在它们如何利用两个反式激活结构域方面有很大差异。通过对动态时程数据的模型辅助分析，我们揭示了TA 1和TA 2的基因特异性协同和冗余。考虑到翻译后修饰控制TA 1活性和对共激活因子的内在亲和力决定TA 2活性，差异TA逻辑表明内源性RelA靶基因的上下文依赖性与上下文无关性控制。虽然一些炎症引发剂似乎需要共刺激TA 1激活，炎症消退是NF-κ B RelA核心反应的一部分。
Nuclear factor kappa B (NF-kappa B) RelA is the potent transcriptional activator of inflammatory response genes. We stringently defined a list of direct RelA target genes by integrating physical (chromatin immunoprecipitation sequencing [ChIP-seq]) and functional (RNA sequencing [RNA-seq] in knockouts) datasets. We then dissected each gene's regulatory strategy by testing RelA variants in a primary-cell genetic-complementation assay. All endogenous target genes require RelA to make DNA-base-specific contacts, and none are activatable by the DNA binding domain alone. However, endogenous target genes differ widely in how they employ the two transactivation domains. Through model-aided analysis of the dynamic time-course data, we reveal the gene-specific synergy and redundancy of TA1 and TA2. Given that post-translational modifications control TA1 activity and intrinsic affinity for coactivators determines TA2 activity, the differential TA logics suggests context-dependent versus context-independent control of endogenous RelA-target genes. Although some inflammatory initiators appear to require co-stimulatory TA1 activation, inflammatory resolvers are a part of the NF-kappa B RelA core response.