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.
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