An intronic variant associated with systemic lupus erythematosus changes the binding affinity of Yinyang1 to downregulate WDFY4
An intronic variant associated with systemic lupus erythematosus changes the binding affinity of Yinyang1 to downregulate WDFY4
复制标题
与系统性红斑狼疮相关的内含子变异改变了 Yinyang1 的结合亲和力，从而下调 WDFY4
DOI：
10.1038/gene.2012.33
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发表时间：
2012-10-01
影响因子：
5
通讯作者：
Liu, Q.
中科院分区：
文献类型：
--
作者：
Zhao, H.;Yang, W.;Liu, Q.
最近两项东亚人群的全基因组关联研究揭示了WDFY 4/LRRC 18中与系统性红斑狼疮（SLE）相关的三种遗传变异。为了鉴定导致这种疾病易感性的基因，我们检测了SLE患者和健康对照组中WDFY 4和LRRC 18的mRNA表达。与对照组相比，SLE患者中WDFY 4显著下调。我们使用等位基因表达和双荧光素酶测定来鉴定功能变体。rs 877819 A的转录活性低于-G等位基因。电泳迁移率改变和超迁移率分析显示转录因子Yinyang 1（YY 1）与rs 877819结合，与A等位基因的亲和力较低，这解释了转录活性降低的原因。YY 1小干扰RNA敲除、过表达和染色质免疫沉淀实验进一步证实了这一效应。WDFY 4中rs 877819可能是通过减少YY 1的结合和下调WDFY 4的表达而与SLE相关的功能位点。
Two recent genome-wide association studies of East Asian populations revealed three genetic variants in WDFY4/LRRC18 associated with systemic lupus erythematosus (SLE). To identify the gene contributing to this disease susceptibility, we examined the mRNA expression of WDFY4 and LRRC18 in patients with SLE and healthy controls. WDFY4 was significantly downregulated in SLE patients as compared with controls. We used allelic expression and dual-luciferase assays to identify the functional variant. Transcriptional activity was lower for the rs877819A than-G allele. Electrophoretic mobility shift and supershift assays revealed that the transcription factor Yinyang1 (YY1) binds to rs877819, with lower affinity to the A allele, which explained the reduced transcriptional activity. This effect was further confirmed by YY1 small interfering RNA knockdown, overexpression and chromatin immunoprecipitation experiments. rs877819 in WDFY4 might be the functional site associated with SLE by reduced binding of YY1 and downregulating WDFY4 expression.