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首页> 外文期刊>Molecular and Cellular Biology >Genome-Wide Approaches Reveal Functional Interleukin-4-Inducible STAT6 Binding to the Vascular Cell Adhesion Molecule 1 Promoter
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Genome-Wide Approaches Reveal Functional Interleukin-4-Inducible STAT6 Binding to the Vascular Cell Adhesion Molecule 1 Promoter

机译：全基因组方法揭示功能性白介素4诱导STAT6绑定到血管细胞粘附分子1启动子。

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Endothelial cell activation and dysfunction underlie many vascular disorders, including atherosclerosis and inflammation. Here, we show that interleukin-4 (IL-4) markedly induced vascular cell adhesion molecule 1 (VCAM-1), both in cultured endothelial cells and in the intact endothelium in mice. Combined treatment with IL-4 and tumor necrosis factor alpha (TNF-α) resulted in further, sustained induction of VCAM-1 expression. IL-4-mediated induction of VCAM-1 and secondary monocyte adhesion was predominantly regulated by the transcription factor STAT6. Genome-wide survey of IL-4-mediated STAT6 binding from sequential chromatin-immunoprecipitation with deep sequencing (chromatin immunoprecipitation sequencing [ChIP-seq]) in endothelial cells revealed regions of transient and sustained transcription factor binding. Through the combination of DNA microarrays and ChIP-seq at the same time points, the majority of IL-4-responsive genes were shown to be STAT6 dependent and associated with direct STAT6 binding to their promoter. IL-4-mediated stable binding of STAT6 led to sustained target gene expression. Moreover, our strategy led to the identification of a novel functionally important STAT6 binding site within 16 kb upstream of the VCAM-1 gene. Taken together, these findings support a critical role for STAT6 in mediating IL-4 signal transduction in endothelial cells. Identification of a novel IL-4-mediated VCAM-1 enhancer may provide a foundation for targeted therapy in vascular disease.
机译：内皮细胞的活化和功能障碍是许多血管疾病的基础，包括动脉粥样硬化和炎症。在这里，我们显示白介素4（IL-4）显着诱导血管内皮细胞粘附分子1（VCAM-1），无论是在培养的内皮细胞中还是在小鼠的完整内皮中。 IL-4和肿瘤坏死因子α（TNF-α）的联合治疗可进一步持续诱导VCAM-1表达。 IL-4介导的VCAM-1诱导和继发性单核细胞粘附主要受转录因子STAT6调控。全基因组范围内对IL-4介导的STAT6结合的调查，涉及到内皮细胞中的顺序染色质免疫沉淀和深度测序（染色质免疫沉淀测序[ChIP-seq]），显示了瞬时和持续转录因子结合的区域。通过在同一时间点结合DNA芯片和ChIP-seq，大多数IL-4响应基因被证明是STAT6依赖性的，并与STAT6直接结合其启动子有关。 IL-4介导的STAT6稳定结合导致持续的靶基因表达。此外，我们的策略导致在VCAM-1基因上游16 kb内鉴定出一个新的功能上重要的STAT6结合位点。综上所述，这些发现支持STAT6在介导内皮细胞中IL-4信号转导中的关键作用。新型IL-4介导的VCAM-1增强剂的鉴定可为血管疾病的靶向治疗提供基础。

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