Glucocorticoid receptor represses proinflammatory genes at distinct steps of the transcription cycle
Glucocorticoid receptor represses proinflammatory genes at distinct steps of the transcription cycle
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DOI：
10.1073/pnas.1309898110
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发表时间：
2013-09-03
影响因子：
11.1
通讯作者：
Rogatsky, Inez
中科院分区：
文献类型：
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作者：
Gupte, Rebecca;Muse, Ginger W.;Rogatsky, Inez
糖皮质激素的广泛抗炎作用是由糖皮质激素受体 (GR) 介导的，GR 是核受体超家族的配体依赖性转录因子。 GR 与其辅阻遏物 GR 相互作用蛋白 1 (GRIP1) 结合，与 DNA 结合激活蛋白 1 和 NF-κ B 结合，抑制其目标促炎细胞因子基因的转录。然而，这些靶基因根据对其激活进行速率限制的转录周期步骤分为不同的类别：一些是通过 RNA 聚合酶 II (PolII) 招募和启动来控制的，而另一些则经历信号诱导的暂停延伸复合物释放以产生有效的 RNA 合成。这些基因是否受到 GR 的差异调节尚不清楚。在这里，我们报告说，在初级巨噬细胞中起始控制的炎症基因中，GR 抑制 LPS 诱导的 PolII 占据。相反，在延伸控制基因中，GR 不影响 PolII 募集或转录起始，而是以 GRIP1 依赖性方式促进暂停诱导负延伸因子的积累。一致地，在负延伸因子缺乏的巨噬细胞中，GR依赖性延伸控制基因的抑制被特别消除。因此，GR:GRIP1 使用不同的机制在转录周期的不同阶段抑制炎症基因。
Widespread anti-inflammatory actions of glucocorticoid hormones are mediated by the glucocorticoid receptor (GR), a ligand-dependent transcription factor of the nuclear receptor superfamily. In conjunction with its corepressor GR-interacting protein-1 (GRIP1), GR tethers to the DNA-bound activator protein-1 and NF-kappa B and represses transcription of their target proinflammatory cytokine genes. However, these target genes fall into distinct classes depending on the step of the transcription cycle that is rate-limiting for their activation: Some are controlled through RNA polymerase II (PolII) recruitment and initiation, whereas others undergo signal-induced release of paused elongation complexes into productive RNA synthesis. Whether these genes are differentially regulated by GR is unknown. Here we report that, at the initiation-controlled inflammatory genes in primary macrophages, GR inhibited LPS-induced PolII occupancy. In contrast, at the elongation-controlled genes, GR did not affect PolII recruitment or transcription initiation but promoted, in a GRIP1-dependent manner, the accumulation of the pause-inducing negative elongation factor. Consistently, GR-dependent repression of elongation-controlled genes was abolished specifically in negative elongation factor-deficient macrophages. Thus, GR: GRIP1 use distinct mechanisms to repress inflammatory genes at different stages of the transcription cycle.