Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-κB-dependent inflammatory genes -: Relevance to diabetes and inflammation
Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-κB-dependent inflammatory genes -: Relevance to diabetes and inflammation
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DOI：
10.1074/jbc.m802800200
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发表时间：
2008-09-26
影响因子：
4.8
通讯作者：
Natarajan, Rama
中科院分区：
文献类型：
--
作者：
Li, Yan;Reddy, Marpadga A.;Natarajan, Rama
核因子κ B （nf - κ B）调节炎症基因，如tnf - α（肿瘤坏死因子α），在炎症性疾病的发病机制中发挥关键作用，包括糖尿病和代谢综合征。然而，核染色质机制尚不清楚。我们在这里报道，染色质组蛋白h3 -赖氨酸4甲基转移酶SET7/9是NF-kappa b的一种新型共激活因子。在单核细胞中，用小干扰rna沉默SET7/9的基因可显著抑制tnf - α诱导的炎症基因和这些启动子上的组蛋白h3 -赖氨酸4甲基化，以及单核细胞对内皮细胞或平滑肌细胞的粘附。染色质免疫沉淀显示SET7/9小干扰RNA可以减少tnf α诱导的NF-kappa B p65对炎症基因启动子的募集。在SET7/9敲除的单核细胞中，晚期糖基化终产物受体配体对炎症基因的诱导也减弱了。此外，我们还观察到糖尿病小鼠巨噬细胞中炎症基因表达和SET7/9募集增加。芯片分析显示，在tnf α刺激的单核细胞中，通过SET7/9缺失，25% NF-kappa B下游基因（包括组蛋白h3 -赖氨酸27去甲基化酶JMJD3）的诱导减弱。这些结果证明SET7/9在炎症和糖尿病中的新作用。
Nuclear factor kappa-B (NF-kappa B)-regulated inflammatory genes, such as TNF-alpha(tumor necrosis factor-alpha), play key roles in the pathogenesis of inflammatory diseases, including diabetes and the metabolic syndrome. However, the nuclear chromatin mechanisms are unclear. We report here that the chromatin histone H3-lysine 4 methyltransferase, SET7/9, is a novel coactivator of NF-kappa B. Gene silencing of SET7/9 with small interfering RNAs in monocytes significantly inhibited TNF-alpha-induced inflammatory genes and histone H3-lysine 4 methylation on these promoters, as well as monocyte adhesion to endothelial or smooth muscle cells. Chromatin immunoprecipitation revealed that SET7/9 small interfering RNA could reduce TNF-alpha-induced recruitment of NF-kappa B p65 to inflammatory gene promoters. Inflammatory gene induction by ligands of the receptor for advanced glycation end products was also attenuated in SET7/9 knockdown monocytes. In addition, we also observed increased inflammatory gene expression and SET7/9 recruitment in macrophages from diabetic mice. Microarray profiling revealed that, in TNF-alpha-stimulated monocytes, the induction of 25% NF-kappa B downstream genes, including the histone H3-lysine 27 demethylase JMJD3, was attenuated by SET7/9 depletion. These results demonstrate a novel role for SET7/9 in inflammation and diabetes.