Epigenetic Regulation of the IL-13-induced Human Eotaxin-3 Gene by CREB-binding Protein-mediated Histone 3 Acetylation
Epigenetic Regulation of the IL-13-induced Human Eotaxin-3 Gene by CREB-binding Protein-mediated Histone 3 Acetylation
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DOI：
10.1074/jbc.m110.210724
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发表时间：
2011-04-15
影响因子：
4.8
通讯作者：
Rothenberg, Marc E.
中科院分区：
文献类型：
--
作者：
Lim, Eun Jin;Lu, Thomas X.;Rothenberg, Marc E.
各种慢性炎症性疾病的病因已被归因于遗传和环境因素的相互作用。在此，我们确定了慢性过敏性炎症发病机制中表观遗传调控和IL-13驱动的嗜酸性粒细胞趋化因子-3之间的联系。我们首先证明了Eotaxin-3启动子中的cAMP反应元件（CRE）位点影响IL-13诱导的Eotaxin-3启动子活性。此外，CRE结合蛋白结合蛋白（CBP），组蛋白乙酰转移酶，诱导基线和IL-13诱导的嗜酸性粒细胞趋化因子-3启动子活性。此外，IL-13处理促进了整体组蛋白3乙酰化以及含有CBP和STAT 6的复合物的形成，以及随后在嗜酸细胞活化趋化因子-3启动子处组蛋白3的乙酰化。CBP基因沉默降低IL-13诱导的eotaxin-3转录。相反，抑制组蛋白去乙酰化增加IL-13诱导的嗜酸性粒细胞趋化因子-3的产生。临床研究表明，在过敏性炎症患者的发炎组织中，组蛋白3的整体乙酰化显著增加。总的来说，这些结果确定了涉及CBP和染色质重塑调节IL-13诱导的趋化因子转录的表观遗传机制。
The etiology of a variety of chronic inflammatory disorders has been attributed to the interaction of genetic and environmental factors. Herein, we identified a link between epigenetic regulation and IL-13-driven eotaxin-3 in the pathogenesis of chronic allergic inflammation. We first demonstrated that the cAMP-responsive element (CRE) site in the eotaxin-3 promoter affects IL-13-induced eotaxin-3 promoter activity. Furthermore, the CRE-binding protein-binding protein (CBP), a histone acetyltransferase, induced base-line and IL-13-induced eotaxin-3 promoter activity. Additionally, IL-13 treatment promoted global histone 3 acetylation as well as the formation of a complex containing CBP and STAT6 and the subsequent acetylation of histone 3 at the eotaxin-3 promoter. CBP gene silencing decreased IL-13-induced transcription of eotaxin-3. Conversely, inhibition of histone deacetylation increased IL-13-induced eotaxin-3 production. Clinical studies demonstrated markedly increased global acetylation of histone 3 in the inflamed tissue of patients with allergic inflammation. Collectively, these results identify an epigenetic mechanism involving CBP and chromatin remodeling in regulating IL-13-induced chemokine transcription.