ALLELE SPECIFIC TRANSCRIPTIONAL CONTROL OF HLA DQ EXPRESSION

HLA II类基因与胰岛素依赖型糖尿病高度相关，这是一种与胰岛素依赖型糖尿病相关的特征。 多态性序列存在于特定的“风险等位基因”中。值得注意的是， 多态性延伸通过上游基因序列，包括 启动子和相关的转录调控元件。在这 多态性调控区，“x- 框”元件对应于基因座特异性和等位基因的差异， 特异转录一个合理的模型来解释这些非- HLA II类表达的协调方面是保守蛋白， 与启动子区中共有元件的相互作用是 基因表达的先决条件，能够与较小的 基因座和等位基因序列变异特异性因子子集 集中在x-box区域，这是通过加法来实现的， 对更一般的II类监管复合体的干扰。我们提出 为了表征这些基因座和等位基因特异性相互作用， 与IDDM易感性有关的HLA-DQB 1基因我们将 鉴定识别多态性位点的DNA结合蛋白 与HLA-DQB 1启动子，并研究其作用机制，使用 转录复合物的特异性靶位点抑制剂。我们将 分析不同细胞间DQB 1内源基因表达差异 不同疾病表型的患者，特别是在 风险“非进展者”、迟发性IDDM和自身抗体阳性NIDDM， 与项目3和项目4一起。我们将深入分析 YY 1，我们已经确定的第一个转录因子， DQB 1表达，其以等位基因特异性方式结合DQ启动子。在 结合项目2，我们将评估更改DQ的影响 确定的GAD-Ab复合物的抗原呈递上的表达。我们将 分析病毒蛋白与YY 1之间的相互作用 反式激活结构域，以确定在环境刺激， 病毒调节DQ表达和功能。理解非- HLA II类表达的协调方面代表了新的 与细胞发育和分化相关的信息，以及 以及促进胰岛素依赖型糖尿病和其他HLA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.