TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation.
TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation.
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DOI：
10.1038/ncomms9900
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发表时间：
2015-11-23
影响因子：
16.6
通讯作者：
Romeo PH
中科院分区：
文献类型：
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作者：
Ferri F;Parcelier A;Petit V;Gallouet AS;Lewandowski D;Dalloz M;van den Heuvel A;Kolovos P;Soler E;Squadrito ML;De Palma M;Davidson I;Rousselet G;Romeo PH
尽管干扰素-β 基因 (Ifnb1) 在病毒或细菌感染期间很重要，但人们对激活巨噬细胞中干扰素-β 基因 (Ifnb1) 的转录调控仍知之甚少。在这里，我们报告 TRIM33 缺陷导致 Ifnb1 在巨噬细胞中 Toll 样受体介导的激活的晚期阶段持续高表达，但在成纤维细胞中则不然。在巨噬细胞中，TRIM33 被 PU.1 招募到一个保守区域，即 Ifnb1 控制元件 (ICE)，位于 Ifnb1 转录起始位点上游 15 kb 处。 ICE 通过 TRIM33 独立的染色质环与 Ifnb1 组成型相互作用。在巨噬细胞脂多糖激活的后期，TRIM33 与 ICE 结合，调节 Ifnb1 增强小体负载，控制 Ifnb1 染色质结构并通过阻止 CBP/p300 的募集来抑制 Ifnb1 基因转录。这些结果描述了一种以前未知的巨噬细胞特异性调节 Ifnb1 转录的机制，其中 TRIM33 对于 Ifnb1 基因转录关闭至关重要。 巨噬细胞中干扰素-β 基因 (Ifnb1) 的转录调控是一个关键的免疫事件。在这里，费里等人。结果表明，在巨噬细胞激活的后期，TRIM33 与远端阻遏元件结合，通过阻止 CBP/p300 的募集来抑制 Ifnb1 转录。
Despite its importance during viral or bacterial infections, transcriptional regulation of the interferon-β gene (Ifnb1) in activated macrophages is only partially understood. Here we report that TRIM33 deficiency results in high, sustained expression of Ifnb1 at late stages of toll-like receptor-mediated activation in macrophages but not in fibroblasts. In macrophages, TRIM33 is recruited by PU.1 to a conserved region, the Ifnb1 Control Element (ICE), located 15 kb upstream of the Ifnb1 transcription start site. ICE constitutively interacts with Ifnb1 through a TRIM33-independent chromatin loop. At late phases of lipopolysaccharide activation of macrophages, TRIM33 is bound to ICE, regulates Ifnb1 enhanceosome loading, controls Ifnb1 chromatin structure and represses Ifnb1 gene transcription by preventing recruitment of CBP/p300. These results characterize a previously unknown mechanism of macrophage-specific regulation of Ifnb1 transcription whereby TRIM33 is critical for Ifnb1 gene transcription shutdown. Transcriptional regulation of the interferon-β gene (Ifnb1) in macrophages is a critical immune event. Here, Ferri et al. show that, at late phases of macrophages activation, TRIM33 bound to a distal repressor element suppresses Ifnb1 transcription by preventing recruitment of CBP/p300.