Increased production of the Th2 cytokine IL-4 is now known to be a hallmark of asthma and other allergic disorders. Therefore, a thorough understanding of the factors that regulate IL-4 gene expression is essential. IL-4 expression is controlled at the level of gene transcription by the coordinated actions of multiple transcription factors that bind to a complex promoter region. In addition, full expression of IL-4 in polarized Th2 cells requires still poorly understood chromatin remodeling events. In this proposal, we aim to explore a novel transcription factor and cis-elements that regulate IL-4 gene transcription and chromatin remodeling in T cells. We will first expand on our novel observation that the zinc-finger factor Yin-Yang-1 (YY-1) activates IL-4 gene transcription and determine the contribution of four YY-1 binding sites to IL-4 promoter architecture and the formation of an IL-4 promoter enhance some. We will study a novel signal transduction pathway and test the hypothesis that YY-1 is inducibly acetylated in activated T cells. We found that YY-1 expression is strikingly enhanced in the allergic airway, and will use mouse strains carrying targeted deletions of YY-1 to test the hypothesis that YY-1 is required for in vivo Th2 responses and allergic airway inflammation. Additionally, we will systematically analyze the expression of YY-1 and other Th transcription factors in the airway and peribronchial lymph nodes in the human lung. Finally, given YY-1's ability to interact with different histone modifying enzymes, and the IL-4 promoter and other regulatory elements in vivo, we will test the hypothesis that histone acetylation and/or methylation at the Th2 cytokine locus are dependent upon YY-1. Taken together, our studies will define novel factors and pathways involved in the molecular regulation of Th2 gene expression and in the pulmonary response to allergen. ? ?
