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An Inducible Enhancer Required for Il12b Promoter Activity in an Insulated Chromatin Environment

机译：绝缘染色质环境中Il12b启动子活性所需的诱导型增强子

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Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that serve as critical regulators of T helper cell development. The Il12b gene, which encodes the p40 subunit of both IL-12 and IL-23, is expressed in macrophages and dendritic cells following induction by bacterial products. Although the Il12b promoter, like the promoters of most proinflammatory genes, can support transcriptional induction in typical transfection assays, we show that it is not sufficient for transcription in an insulated chromatin environment. Using a DNase I hypersensitivity assay, two potential distal control regions were identified. One region, DNase I-hypersensitive site 1 (HSS1), located 10 kb upstream of the transcription start site, exhibited hypersensitivity only in stimulated macrophages. In an insulated environment, a 105-bp fragment spanning HSS1 was sufficient for transcription when combined with the Il12b promoter. Although several elements are likely to contribute to activity of the endogenous HSS1 enhancer, including an evolutionarily conserved binding site for C/EBP proteins, the only element required for activity in transient- and stable-transfection assays bound Oct-1 and Oct-2, both of which are expressed constitutively in macrophages. Oct-1 and Oct-2 were recruited to the enhancer upon macrophage stimulation, and the Oct site appeared important for nucleosome remodeling at HSS1. These results suggest that the HSS1 enhancer and Oct proteins play central roles in Il12b induction upon macrophage activation.
机译：白介素12（IL-12）和IL-23是异二聚体细胞因子，可作为T辅助细胞发育的关键调节剂。编码IL-12和IL-23的p40亚基的 Il12b 基因在被细菌产物诱导后在巨噬细胞和树突状细胞中表达。尽管 Il12b 启动子，像大多数促炎基因的启动子一样，可以在典型的转染实验中支持转录诱导，但我们证明在绝缘染色质环境中，这不足以实现转录。使用DNase I超敏性分析，鉴定了两个潜在的远端对照区域。位于转录起始位点上游10 kb的一个区域DNase I超敏性位点1（HSS1）仅在受刺激的巨噬细胞中表现出超敏性。在绝缘环境中，与 Il12b 启动子结合时，跨过HSS1的105 bp片段足以进行转录。尽管可能有几种元素有助于内源HSS1增强子的活性，包括C / EBP蛋白在进化上保守的结合位点，但瞬时和稳定转染测定法中活性所需的唯一元素是与Oct-1和Oct-2结合，两者均在巨噬细胞中组成性表达。在巨噬细胞刺激下，Oct-1和Oct-2被募集到增强子中，Oct位点似乎对HSS1的核小体重塑很重要。这些结果表明HSS1增强子和Oct蛋白在巨噬细胞激活后在 Il12b 诱导中起核心作用。

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