SP140 regulates the expression of immune-related genes associated with multiple sclerosis and other autoimmune diseases by NF-κB inhibition
SP140 regulates the expression of immune-related genes associated with multiple sclerosis and other autoimmune diseases by NF-κB inhibition
复制标题
DOI：
10.1093/hmg/ddy284
复制
发表时间：
2018-12-01
影响因子：
3.5
通讯作者：
Matesanz, Fuencisla
中科院分区：
文献类型：
--
作者：
Karaky, Mohamad;Fedetz, Maria;Matesanz, Fuencisla
全基因组关联研究（genome-wide association studies，GWAS）发现SP140位点与多发性硬化（multiple sclerosis，MS）及其他自身免疫性疾病相关。这些关联的因果变体（rs 28445040-T）改变了SP140基因转录本的剪接，从而降低了蛋白质表达。我们的目的是了解为什么风险变异产生的SP140表达的减少可以增加对MS的易感性。为此，我们通过RNA测序（RNA-seq）分析确定了淋巴母细胞系（LCL）中SP140沉默后的差异表达基因。我们分析了这些基因的基因本体论（GO），比较转录组配置文件，这些基因的启动子中的转录因子（TF）的富集和共定位与GWAS风险变异。我们还通过荧光素酶报告系统监测了SP 140沉默细胞中活化B细胞核因子κ轻链增强子（NF-κ B）的活性。我们鉴定了SP140沉默LCL中100个上调基因和22个下调基因。GO分析显示，受SP140影响的基因参与调节细胞因子产生、炎症反应和细胞-细胞粘附。我们观察到NF-κ B B TF在SP 140沉默细胞系中上调基因启动子中的富集和NF-κ B增加的活性。我们发现，在GWAS检测的MS（14.63倍），克罗恩病（4.82倍）和炎症性肠病（4.47倍）的风险位点中，SP140调节的基因富集，在其他无关的免疫疾病中未观察到。我们的研究结果表明，SP140是一个重要的抑制因子的基因参与炎症，这表明，减少SP140的表达，促进rs 28445040-T风险变异，可能会导致上调这些基因的NF-κ B抑制B细胞的手段。
SP140 locus has been associated with multiple sclerosis (MS) as well as other autoimmune diseases by genome-wide association studies (GWAS). The causal variant of these associations (rs28445040-T) alters the splicing of the SP140 gene transcripts reducing the protein expression. We aimed to understand why the reduction of SP140 expression produced by the risk variant can increase the susceptibility to MS. To this end, we determined by RNA sequencing (RNA-seq) analysis the differentially expressed genes after SP140 silencing in lymphoblastoid cell lines (LCLs). We analyzed these genes by gene ontology (GO), comparative transcriptome profiles, enrichment of transcription factors (TFs) in the promoters of these genes and colocalization with GWAS risk variants. We also monitored the activity of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) in SP140-silenced cells by luciferase reporter system. We identified 100 genes that were up-regulated and 22 genes down-regulated in SP140-silenced LCLs. GO analysis revealed that genes affected by SP140 were involved in regulation of cytokine production, inflammatory response and cell-cell adhesion. We observed enrichment of NF-kappa B TF in the promoter of up-regulated genes and NF-kappa B-increased activity in SP140-silenced cell lines. We showed enrichment of genes regulated by SP140 in GWAS-detected risk loci for MS (14.63 folds), Crohn's disease (4.82 folds) and inflammatory bowel disease (4.47 folds), not observed in other unrelated immune diseases. Our findings showed that SP140 is an important repressor of genes implicated in inflammation, suggesting that decreased expression of SP140, promoted by the rs28445040-T risk variant, may lead to up-regulation of these genes by means of NF-kappa B inhibition in B cells.