Yin-Yang-1:a novel transcription factor in Th responses

描述(由申请人提供)：Th2细胞因子IL-4的产生增加现在被认为是哮喘和其他过敏性疾病的标志。因此，深入了解调节IL-4基因表达的因素是至关重要的。IL-4的表达受多个转录因子协同作用的调控，这些转录因子结合在一个复杂的启动子区域。此外，IL-4在极化的Th2细胞中的充分表达需要仍然知之甚少的染色质重构事件。在这项建议中，我们旨在探索一种新的转录因子和顺式元件来调节T细胞中IL-4基因的转录和染色质重塑。我们将首先扩展我们的新观察，即锌指因子阴阳-1(YY-1)激活IL-4基因转录，并确定四个YY-1结合位点对IL-4启动子结构的贡献以及IL-4启动子的形成增强一些。我们将研究一种新的信号转导途径，并验证YY-1在激活的T细胞中被诱导乙酰化的假设。我们发现YY-1在过敏性呼吸道中的表达显著增强，并将使用携带YY-1靶向缺失的小鼠品系来验证YY-1在体内Th2反应和过敏性呼吸道炎症中所需的假设。此外，我们还将系统分析YY-1和其他Th转录因子在人肺的呼吸道和支气管周淋巴结中的表达。最后，鉴于YY-1‘S能够与不同的组蛋白修饰酶相互作用，以及体内IL-4启动子和其他调控元件，我们将验证组蛋白乙酰化和/或Th2细胞因子基因座甲基化依赖于YY-1的假设。综上所述，我们的研究将确定参与Th2基因表达的分子调控和肺对变应原反应的新因素和新途径。

DESCRIPTION (provided by applicant): 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.