Bcl-6 and NF-κB cistromes mediate opposing regulation of the innate immune response
Bcl-6 and NF-κB cistromes mediate opposing regulation of the innate immune response
复制标题
DOI：
10.1101/gad.1998010
复制
发表时间：
2010-12-15
影响因子：
10.5
通讯作者：
Evans, Ronald M.
中科院分区：
文献类型：
--
作者：
Barish, Grant D.;Yu, Ruth T.;Evans, Ronald M.
在巨噬细胞中，Toll样受体(TLRs)是关键的感受器，通过核因子-kappa B基因网络触发信号级联激活炎症程序。然而，以TLR/NF-kappa B激活为靶点的基因组网络以及它被抑制以终止激活和重新建立静止的分子基础还知之甚少。在这里，使用染色质免疫沉淀测序(ChIP-seq)，我们定义了核因子-kappa B序列，它由31,070个顺式作用结合位点组成，响应内毒素(LPS)诱导的信号。此外，我们还证明了转录抑制因子B细胞淋巴瘤6(Bcl6)调控TLR4调节的转录组的近三分之一，并且TLR4激活后90%的Bcl6转录组崩溃。Bcl6缺乏的巨噬细胞对内毒素高度敏感，利用比较芯片序列分析，我们发现在核小体距离内，在刺激的巨噬细胞中，近一半的Bcl6结合部位的Bcl6和NFkappaB交叉，以促进局部染色质的相反的表观遗传修饰。这些结果揭示了一种控制先天性免疫反应的基因组策略，在该策略中，抑制性和诱导性池通过表观标记的顺式调节元件在巨噬细胞静止和激活之间建立动态平衡。
In the macrophage, toll-like receptors (TLRs) are key sensors that trigger signaling cascades to activate inflammatory programs via the NF-kappa B gene network. However, the genomic network targeted by TLR/NF-kappa B activation and the molecular basis by which it is restrained to terminate activation and re-establish quiescence is poorly understood. Here, using chromatin immunoprecipitation sequencing (ChIP-seq), we define the NF-kappa B cistrome, which is comprised of 31,070 cis-acting binding sites responsive to lipopolysaccharide (LPS)-induced signaling. In addition, we demonstrate that the transcriptional repressor B-cell lymphoma 6 (Bcl-6) regulates nearly a third of the Tlr4-regulated transcriptome, and that 90% of the Bcl-6 cistrome is collapsed following Tlr4 activation. Bcl6-deficient macrophages are acutely hypersensitive to LPS and, using comparative ChIP-seq analyses, we found that the Bcl-6 and NF-kappa B cistromes intersect, within nucleosomal distance, at nearly half of Bcl-6-binding sites in stimulated macrophages to promote opposing epigenetic modifications of the local chromatin. These results reveal a genomic strategy for controlling the innate immune response in which repressive and inductive cistromes establish a dynamic balance between macrophage quiescence and activation via epigenetically marked cis-regulatory elements.