Identification of LncRNA Linc00513 Containing Lupus-Associated Genetic Variants as a Novel Regulator of Interferon Signaling Pathway
Identification of LncRNA Linc00513 Containing Lupus-Associated Genetic Variants as a Novel Regulator of Interferon Signaling Pathway
复制标题
鉴定含有狼疮相关遗传变异的 LncRNA Linc00513 作为干扰素信号通路的新型调节剂。
DOI：
10.3389/fimmu.2018.02967
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发表时间：
2018-12-18
影响因子：
7.3
通讯作者：
Shen, Nan
中科院分区：
文献类型：
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作者：
Xue, Zhixin;Cui, Chaojie;Shen, Nan
系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，其特征是I型干扰素信号增强。高通量技术已经发现了大量的SLE易感性单核苷酸多态性（SNPs），但其中大多数的确切作用仍然未知。功能研究主要集中在编码区的SNPs，对非编码区的SNPs关注有限。长链非编码RNA（IncRNA）是形成免疫应答的重要参与者，并显示与自身免疫性疾病的关系。为了揭示位于SLE相关IncRNA附近的SNPs的作用，我们对SLE患者进行了转录组分析，并将linc 00513鉴定为在启动子区域中含有功能性SLE易感性位点的显著过表达的IncRNA。rs205764的G等位基因和rs547311的A等位基因增强了linc 00513启动子的活性，并与SLE中linc 00513的表达增加有关。我们还鉴定了linc 00513是一种新型的I型干扰素途径的正调节剂，通过促进STAT1和STAT2的磷酸化。在SLE患者中，linc 00513表达升高与IFN评分呈正相关。活动期患者中Linc 00513的表达高于非活动期患者。总之，我们的数据确定了两个功能性启动子变体的linc 00513，有助于增加水平的linc 00513，并赋予SLE的易感性。该研究为SLE的遗传学提供了新的见解，并扩展了IncRNA在SLE发病机制中的作用。
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by augmented type I interferon signaling. High-throughput technologies have identified plenty of SLE susceptibility single-nucleotide polymorphisms (SNPs) yet the exact roles of most of them are still unknown. Functional studies are principally focused on SNPs in the coding regions, with limited attention paid to the SNPs in non-coding regions. Long non-coding RNAs (IncRNAs) are important players in shaping the immune response and show relationship to autoimmune diseases. In order to reveal the role of SNPs located near SLE related IncRNAs, we performed a transcriptome profiling of SLE patients and identified linc00513 as a significantly over expressed IncRNA containing functional SLE susceptibility loci in the promoter region. The risk-associated G allele of rs205764 and A allele of rs547311 enhanced linc00513 promoter activity and related to increased expression of linc00513 in SLE. We also identified linc00513 to be a novel positive regulator of type I interferon pathway by promoting the phosphorylation of STAT1 and STAT2. Elevated linc00513 expression positively correlated with IFN score in SLE patients. Linc00513 expression was higher in active disease patients than those inactive ones. In conclusion, our data identify two functional promoter variants of linc00513 that contribute to increased level of linc00513 and confer susceptibility on SLE. The study provides new insights into the genetics of SLE and extends the role of IncRNAs in the pathogenesis of SLE.