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

描述（由申请人提供）：现在已知Th 2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，彻底了解调节IL-4基因表达的因素是至关重要的。 IL-4的表达在基因转录水平上受到与复杂启动子区结合的多个转录因子的协调作用的控制。 此外，IL-4在极化的Th 2细胞中的完全表达需要仍然知之甚少的染色质重塑事件。 本研究旨在探索一种新的转录因子及其顺式调控元件，以调控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4个YY-1结合位点对IL-4启动子结构的贡献，以及IL-4启动子的形成增强了一些。 我们将研究一种新的信号转导途径，并测试YY-1在活化的T细胞中可诱导乙酰化的假设。 我们发现YY-1的表达在过敏性气道中显著增强，并将使用携带YY-1靶向缺失的小鼠品系来测试YY-1是体内Th 2应答和过敏性气道炎症所需的假设。 此外，我们将系统地分析YY-1和其他Th转录因子在人肺的气道和支气管周围淋巴结中的表达。 最后，考虑到YY-1与不同的组蛋白修饰酶、IL-4启动子和其他体内调控元件相互作用的能力，我们将检验Th 2细胞因子位点的组蛋白乙酰化和/或甲基化依赖于YY-1的假设。 总之，我们的研究将确定新的因素和途径参与分子调控的Th 2基因表达和肺过敏原的反应。

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.