The five NF-κB family members and three nuclear IκB proteins play important biological roles, but the mechanisms by which distinct members of these protein families contribute to selective gene transcription remain poorly understood, especially at a genome-wide scale. Using nascent transcript RNA-seq, we observed considerable overlap between p50-dependent and IκBζ-dependent genes in Toll-like receptor 4 (TLR4)-activated macrophages. Key immunoregulatory genes, including Il6, Il1b, Nos2, Lcn2, and Batf, are among the p50–IκBζ-codependent genes. IκBζ-bound genomic sites are occupied at earlier time points by NF-κB dimers. However, p50–IκBζ codependence does not coincide with preferential binding of either p50 or IκBζ, as RelA co-occupies hundreds of genomic sites with the two proteins. A common feature of p50–IκBζ-codependent genes is a nearby p50/RelA/IκBζ-cobound site exhibiting p50-dependent binding of both RelA and IκBζ. This and other results suggest that IκBζ acts in concert with RelA:p50 heterodimers. Notably, p50–IκBζ-codependent genes comprise a high percentage of genes exhibiting the greatest differential expression between TLR4-stimulated and tumor necrosis factor receptor (TNFR)-stimulated macrophages. Thus, our genome-centric analysis reveals a defined p50–IκBζ pathway that selectively activates a set of key immunoregulatory genes and serves as an important contributor to differential TNFR and TLR4 responses.

中文翻译：

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通过 NF-κB p50–IκBζ 通路选择性调节特定的炎症和免疫调节基因子集


五个 NF-κB 家族成员和三个核 IκB 蛋白发挥着重要的生物学作用，但这些蛋白家族的不同成员促进选择性基因转录的机制仍然知之甚少，尤其是在全基因组范围内。使用新生转录本 RNA-seq，我们观察到 Toll 样受体 4 (TLR4) 激活的巨噬细胞中 p50 依赖性基因和 IκB z 依赖性基因之间存在相当大的重叠。关键的免疫调节基因，包括 Il6、Il1b、Nos2、Lcn2 和 Batf，都属于 p50-IκB z 共依赖性基因。 IκBδ 结合的基因组位点在较早的时间点被 NF-κB 二聚体占据。然而，p50-IκB z 的共依赖性与 p50 或 IκB z 的优先结合并不相符，因为 RelA 与这两种蛋白质共同占据数百个基因组位点。 p50-IκB z 共依赖性基因的一个共同特征是附近的 p50/RelA/IκB z 共结合位点表现出 RelA 和 IκB z 的 p50 依赖性结合。该结果和其他结果表明 IκB z 与 RelA:p50 异二聚体协同作用。值得注意的是，p50-IκBδ 共依赖性基因包含很高比例的基因，这些基因在 TLR4 刺激的巨噬细胞和肿瘤坏死因子受体 (TNFR) 刺激的巨噬细胞之间表现出最大的差异表达。因此，我们以基因组为中心的分析揭示了一个明确的 p50–IκBζ 通路，该通路选择性地激活一组关键的免疫调节基因，并作为差异 TNFR 和 TLR4 反应的重要贡献者。