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首页> 外文期刊>Gene expression >A promoter polymorphism in the central MHC gene, IKBL, influences the binding of transcription factors USF1 and E47 on disease-associated haplotypes.
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A promoter polymorphism in the central MHC gene, IKBL, influences the binding of transcription factors USF1 and E47 on disease-associated haplotypes.

机译：中央MHC基因IKBL中的启动子多态性影响转录因子USF1和E47与疾病相关的单倍型的结合。

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The human major histocompatibility complex (MHC) contains genes that affect susceptibility to numerous immunopathological diseases. We propose that genes in the central MHC between TNFA and HLA-B explain associations between the 8.1 haplotype (HLA-A1, B8, DR3) and disease. IKBL encodes a protein resembling members of the IkappaB protein family that regulate bioavailability of NFkappaB. We have identified two polymorphisms in the 500 bp upstream of the transcription start site of IKBL that distinguish the 8.1 haplotype from the resistant 7.1 haplotype (HLA-A3, B7, DR15). A single nucleotide polymorphism at -62 disrupts a putative E-box binding sequence. To investigate binding of transcription factors in vitro, we exposed 32P-labeled DNA fragments carrying both alleles to nuclear extracts, showing allele-specific binding of nuclear proteins from Jurkat cells but not from other lineages. Supershift studies using Jurkat nuclear extract showed that the E-box protein, E47, and ubiquitously expressed transcription factor USF1 bind to the E-box element of the 7.1 haplotype. Transient transfections of luciferase reporter constructs carrying promoter alleles of IKBL into Jurkat cells showed an effect of IKBL-62 alleles. In contrast, alleles at -421 did not affect transcription factor binding or transcription. IKBL was expressed at low levels in Jurkat cells but not in blood mononuclear cells, and expression declined following mitogenic stimulation. The restriction of IKBL expression to Jurkat cells is consistent with evidence that E47 is expressed in thymocytes and suggests IKBL may affect autoimmunity through an effect on T-cell selection.
机译：人类主要组织相容性复合体（MHC）包含影响多种免疫病理疾病易感性的基因。我们建议在TNFA和HLA-B之间的中央MHC基因解释8.1单倍型（HLA-A1，B8，DR3）和疾病之间的关联。 IKBL编码类似于IkappaB蛋白家族成员的蛋白，该蛋白调节NFkappaB的生物利用度。我们在IKBL转录起始位点的上游500 bp中鉴定了两个多态性，将8.1单倍型与抗性7.1单倍型区分开（HLA-A3，B7，DR15）。 -62处的单核苷酸多态性破坏了推定的E-box结合序列。为了研究体外转录因子的结合，我们将携带两个等位基因的32P标记的DNA片段暴露于核提取物中，显示了来自Jurkat细胞而不是其他谱系的核蛋白的等位基因特异性结合。使用Jurkat核提取物的超变速研究表明E-box蛋白E47和普遍表达的转录因子USF1与7.1单倍型的E-box元件结合。携带IKBL启动子等位基因的荧光素酶报告基因构建体的瞬时转染到Jurkat细胞中，显示了IKBL-62等位基因的作用。相反，-421处的等位基因不影响转录因子结合或转录。 IKBL在Jurkat细胞中低水平表达，但在血液单核细胞中不表达，有丝分裂刺激后表达下降。 IKBL表达对Jurkat细胞的限制与在胸腺细胞中表达E47的证据一致，并暗示IKBL可能通过影响T细胞选择来影响自身免疫。

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