ALLELE SPECIFIC TRANSCRIPTIONAL CONTROL OF HLA DQ EXPRESSION

人类白细胞抗原II类基因与IDDM高度相关，这是一种与 在特定的“风险等位基因”中存在多态序列。值得注意的是，这 多态延伸到上游基因序列，包括 启动子及相关转录调控元件。在这个范围内 多态调控区，“x-”及其周围的核苷酸变异 框“元素对应于基因座特定的差异和等位基因- 特定的转录。一个合理的模型来解释这些非 人类白细胞抗原II类表达的协调方面是保守的蛋白质 与启动子区域中的一致元件的相互作用是 基因表达的先决条件，能够与较小的 特定于基因座和等位基因序列变异的因子子集 集中在x-box区域，这是通过相加和 对更一般的II类监管复合体的扰动。我们建议 为了表征这些特定于基因座和等位基因的相互作用 与IDDM易感性有关的HLA-DQB1基因。我们会 识别识别相关多态位点的DNA结合蛋白 与人类白细胞抗原-DQB1启动子结合，研究其作用机制 转录复合体的特定靶点抑制物。我们会 DQB1内源基因在不同细胞间表达的差异分析 疾病表型不同的患者的类型，特别是在- 风险“无进展者”、晚发性IDDM和自身抗体阳性的NIDDM， 结合项目3和4。我们将深入分析 YY1，我们发现的第一个调控转录因子 以等位基因特异性方式结合DQ启动子的DQB1表达。在……里面 结合项目2，我们将评估更改的DQ的影响 明确的GAD-Ab复合体在抗原提呈上的表达。我们会 分析病毒蛋白与YY1病毒的相互作用 确定环境刺激中的反式激活结构域，例如 病毒调节DQ的表达和功能。了解非- 人类白细胞抗原II类表达的协调方面代表着基本的新 与细胞发育和分化相关的信息 至于导致IDDM和其他人类白细胞抗原相关疾病的机制。

HLA class II genes are highly associated with IDDM, a trait linked to the polymorphic sequences present in specific "risk-allele". Remarkably, this polymorphism extends through the upstream gene sequences, including the promoter and related transcriptional regulatory elements. Within this polymorphic regulatory region, nucleotide variation in and around the "x- box" element corresponds to differences in locus-specific and allele- specific transcription. A reasonable model to account for these non- coordinate aspects of HLA class II expression is that conserved protein interaction with consensus elements in the promoter region are a prerequisite for gene expression, capable of interaction with a smaller subset of factors specific for locus and allelic sequence variation concentrated in the x-box region, which is accomplished by additions and perturbations to the more general class II regulatory complex. We propose to characterize these locus-and allele-specific interactions unique to the HLA-DQB1 genes which are implicated in susceptibility to IDDM. We will identify DNA binding proteins which recognize polymorphic sites associated with the HLA-DQB1 promoter, and study their mechanisms of action using specific target site inhibitors of the transcription complex. We will analyze variation in DQB1 endogenous gene expression among different cell types in patients who differ for disease phenotypes, specifically in at- risk "non-progressors", late-onset IDDM, and auto-antibody-positive NIDDM, in conjunction with projects 3 and 4. We will analyze in depth the role of YY1, the first transcription factor which we have identified modulating DQB1 expression which binds DQ promoters in an allele-specific fashion. In conjunction with project 2, we will assess the impact of altered DQ expression on antigen presentation of defined GAD-Ab complexes. We will analyze the interactions between viral proteins and the YY1 transactivation domain to determine in environmental stimuli such as viruses modulate DQ expression and function. Understanding the non- coordinate aspects of HLA class II expression represents fundamental new information relevant to cellular development and differentiation, as well as for mechanisms contributing to IDDM and other HLA-associated diseases.