Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages.
Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages.
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基因特异性机制直接糖皮质激素受体驱动的巨噬细胞炎症反应基因的抑制
DOI：
10.7554/elife.34864
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发表时间：
2018-02-09
期刊：
影响因子：
7.7
通讯作者：
Rogatsky I
中科院分区：
文献类型：
--
作者：
Sacta MA;Tharmalingam B;Coppo M;Rollins DA;Deochand DK;Benjamin B;Yu L;Zhang B;Hu X;Li R;Chinenov Y;Rogatsky I
糖皮质激素受体（GR）有效地抑制巨噬细胞引起的炎症，然而，其潜在的机制仍然不清楚。我们在小鼠巨噬细胞中的全基因组分析表明，通过全局负延伸因子（NELF）解离和RNA聚合酶（Pol）2从早期延伸停滞释放而激活的促炎性暂停基因，以及由从头Pol 2募集诱导的非暂停基因，对急性糖皮质激素抑制同样敏感。此外，在这两种情况下，占主导地位的机制涉及快速GR拴系到p65在NF-κ B结合位点。然而，特别是在暂停的基因，GR激活触发广泛的启动子积累的NELF，与髓细胞特异性NELF缺失赋予糖皮质激素抗性。相反，在非暂停基因中，GR减弱了p300和组蛋白乙酰化的募集，导致BRD 4和介体在启动子和增强子处组装失败，最终阻断Pol 2起始。因此，GR不显示对特定促炎基因类别的偏好;然而，它通过靶向不同的时间事件和转录机制的组分来实现抑制。
The glucocorticoid receptor (GR) potently represses macrophage-elicited inflammation, however, the underlying mechanisms remain obscure. Our genome-wide analysis in mouse macrophages reveals that pro-inflammatory paused genes, activated via global negative elongation factor (NELF) dissociation and RNA Polymerase (Pol)2 release from early elongation arrest, and non-paused genes, induced by de novo Pol2 recruitment, are equally susceptible to acute glucocorticoid repression. Moreover, in both cases the dominant mechanism involves rapid GR tethering to p65 at NF-kB-binding sites. Yet, specifically at paused genes, GR activation triggers widespread promoter accumulation of NELF, with myeloid cell-specific NELF deletion conferring glucocorticoid resistance. Conversely, at non-paused genes, GR attenuates the recruitment of p300 and histone acetylation, leading to a failure to assemble BRD4 and Mediator at promoters and enhancers, ultimately blocking Pol2 initiation. Thus, GR displays no preference for a specific pro-inflammatory gene class; however, it effects repression by targeting distinct temporal events and components of transcriptional machinery.