Signaling Systems Laboratory, Department of Microbiology Immunology, and Molecular Genetics (MIMG), Institute for Quantitative and Computational Biosciences (QCB), Molecular Biology Institute (MBI), University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92037, USA.
Cell Rep. 2020 Feb 25;30(8):2758-2775.e6. doi: 10.1016/j.celrep.2020.01.108.
Nuclear factor κB (NF-κB) 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-κB RelA core response.
核因子 κB（NF-κB）RelA 是炎症反应基因的有效转录激活子。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，严格定义了一组直接 RelA 靶基因列表。然后，我们通过在原代细胞遗传互补测定中测试 RelA 变体，对每个基因的调控策略进行了剖析。所有内源性靶基因都需要 RelA 进行 DNA 碱基特异性接触，并且没有一个可以仅通过 DNA 结合域激活。然而，内源性靶基因在使用两个转录激活结构域方面差异很大。通过对动态时间过程数据的模型辅助分析，我们揭示了 TA1 和 TA2 的基因特异性协同作用和冗余性。鉴于翻译后修饰控制 TA1 活性，并且固有亲和力决定 TA2 活性，因此差异 TA 逻辑表明对内源性 RelA-靶基因的依赖于上下文和独立于上下文的控制。尽管一些炎症启动子似乎需要共刺激 TA1 激活，但炎症调节剂是 NF-κB RelA 核心反应的一部分。
Zotero 插件
