Department of Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore;
Department of Infectious Diseases, Genome Institute of Singapore, Singapore 138672, Singapore; and.
J Immunol. 2018 Aug 15;201(4):1295-1305. doi: 10.4049/jimmunol.1800246. Epub 2018 Jun 29.
NF-κB transcription factors are master regulators of the innate immune response. Activated downstream of pathogen recognition receptors, they regulate the expression of genes to help fight infections as well as recruit the adaptive immune system. NF-κB responds to a wide variety of signals, but the processes by which stimulus specificity is attained remain unclear. In this article, we characterized the response of one NF-κB member, RELA, to four stimuli mimicking infection in human nasopharyngeal epithelial cells. Comparing genome-wide RELA binding, we observed stimulus-specific sites, although most sites overlapped across stimuli. Specifically, the response to poly I:C (mimicking viral dsRNA and signaling through TLR3) induced a distinct RELA profile, binding in the vicinity of antiviral genes and correlating with corresponding gene expression. This group of binding sites was also enriched in IFN regulatory factor motifs and showed overlapping with IFN regulatory factor binding sites. A novel NF-κB target, , was further validated and showed TLR3-specific activation. This work showed that some RELA DNA binding sites varied in activation response following different stimulations and that interaction with more specialized factors could help achieve this stimulus-specific activity. Our data provide a genomic view of regulated host response to different pathogen stimuli.
NF-κB 转录因子是先天免疫反应的主要调节因子。它们在病原体识别受体下游被激活，调节基因的表达，帮助抵抗感染并招募适应性免疫系统。NF-κB 对多种信号做出反应，但刺激特异性如何实现的过程仍不清楚。在本文中，我们描述了一种 NF-κB 成员 RELA 对模拟人鼻咽上皮细胞感染的四种刺激的反应。通过比较全基因组 RELA 结合，我们观察到了刺激特异性位点，尽管大多数位点在各种刺激下重叠。具体来说，poly I:C（模拟病毒双链 RNA 并通过 TLR3 信号传导）的反应诱导了独特的 RELA 谱，在抗病毒基因附近结合，并与相应的基因表达相关。这组结合位点还富含 IFN 调节因子基序，并与 IFN 调节因子结合位点重叠。进一步验证了一个新的 NF-κB 靶基因 ，并显示 TLR3 特异性激活。这项工作表明，一些 RELA DNA 结合位点在不同刺激下的激活反应不同，与更专门的因子相互作用可能有助于实现这种刺激特异性活性。我们的数据提供了对不同病原体刺激下宿主反应的基因组视图。
