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

描述（由申请人提供）：目前已知Th2细胞因子IL-4的产生增加是哮喘和其他过敏性疾病的标志。因此，深入了解IL-4基因表达的调控因素至关重要。IL-4的表达在基因转录水平上受多个转录因子的协同作用控制，这些转录因子结合到一个复杂的启动子区域。此外，IL-4在极化Th2细胞中的充分表达仍然需要染色质重塑事件。在这项提议中，我们旨在探索一种新的转录因子和顺式元件，调节IL-4基因转录和T细胞染色质重塑。我们将首先扩展我们的新观察，即锌指因子阴阳1 （y -1）激活IL-4基因转录，并确定4个y -1结合位点对IL-4启动子结构和IL-4启动子形成的贡献。我们将研究一种新的信号转导途径，并验证YY-1在活化的T细胞中可诱导乙酰化的假设。我们发现y -1在过敏性气道中的表达显著增强，并将使用携带y -1靶向缺失的小鼠品系来验证y -1是体内Th2反应和过敏性气道炎症所必需的假设。此外，我们将系统分析YY-1等Th转录因子在人肺气道和支气管周围淋巴结中的表达。最后，考虑到YY-1在体内与不同组蛋白修饰酶、IL-4启动子和其他调控元件相互作用的能力，我们将验证Th2细胞因子位点组蛋白乙酰化和/或甲基化依赖于YY-1的假设。综上所述，我们的研究将确定涉及Th2基因表达和肺对过敏原反应的分子调控的新因素和途径。

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.