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Long-Range Transcriptional Control of the Il2 Gene by an Intergenic Enhancer

机译:基因间增强子对Il2基因的远程转录控制

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Interleukin-2 (IL-2) is a potent cytokine with roles in both immunity and tolerance. Genetic studies in humans and mice demonstrate a role for Il2 in autoimmune disease susceptibility, and for decades the proximal Il2 upstream regulatory region has served as a paradigm of tissue-specific, inducible gene regulation. In this study, we have identified a novel long-range enhancer of the Il2 gene located 83 kb upstream of the transcription start site. This element can potently enhance Il2 transcription in recombinant reporter assays in vitro, and the native region undergoes chromatin remodeling, transcribes a bidirectional enhancer RNA, and loops to physically interact with the Il2 gene in vivo in a CD28-dependent manner in CD4+ T cells. This cis regulatory element is evolutionarily conserved and is situated near a human single-nucleotide polymorphism (SNP) associated with multiple autoimmune disorders. These results indicate that the regulatory architecture of the Il2 locus is more complex than previously appreciated and suggest a novel molecular basis for the genetic association of Il2 polymorphism with autoimmune disease.
机译:白细胞介素2(IL-2)是一种有效的细胞因子,在免疫和耐受方面均具有作用。人类和小鼠的遗传研究表明 Il2 在自身免疫疾病易感性中的作用,近几十年来, Il2 上游调节区域一直是组织特异性,可诱导的范例基因调控。在这项研究中,我们已经确定了 Il2 基因的新型远程增强子,位于转录起始位点上游83 kb。该元素可以在体外的重组报告子测定中有效增强 Il2 转录,并且天然区域经历了染色质重塑,转录了双向增强子RNA,并形成环以与<在CD4 + T细胞中以CD28依赖性方式表达em> Il2 体内基因。该 cis 调控元件在进化上是保守的,位于与多种自身免疫性疾病相关的人单核苷酸多态性(SNP)附近。这些结果表明, Il2 基因座的调控结构比以前认为的更为复杂,并为 Il2 多态性与自身免疫性疾病的遗传关联提供了新的分子基础。

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