Cytokine-induced epigenetic changes during chronic lung disease

描述(申请人提供)：免疫反应的一个挥之不去的谜题是，某些免疫/炎症细胞如何“记住”它们是否应该主动转录特定的基因，这将有助于它们参与给定的炎症反应。我们的实验室正在研究新的表观遗传学变化，这种变化是通过组蛋白的翻译后修饰诱导的，作为调节免疫细胞衍生介质在肺部炎症启动和维持期间表达谱的机制。我们发现，在Th1或Th2型细胞因子存在的情况下，组蛋白H3和H4的氨基末端发生动态乙酰化和/或甲基化事件，直接调节染色质结构，决定转录因子对特定启动子的可及性。在……里面 在这一应用中，我们将利用已建立的具有不同Th1或Th2表型的肺部炎症模型，来研究细胞因子指导的、基于表观遗传学的新机制，这些机制指导免疫细胞表型支持肺病理。我们的初步数据支持表观遗传机制在维持炎症表型中的关键作用。我们假设，在肺部疾病的维持过程中，决定特定免疫细胞亚群表型的极化细胞因子环境直接诱导细胞发生特定的表观遗传学变化，进而维持疾病慢性化所需的细胞特异性转录程序。这一假说将通过下列特定目的来研究：1)研究由与Th1或Th2型肺免疫反应相关的主要细胞因子环境控制的细胞特异性表观遗传学变化；2)利用条件基因敲除小鼠模型，检验组蛋白甲基转移酶MLL和组蛋白去甲基酶JMJD3在Th1或Th2依赖的肺部炎症发展中的机制作用；3)评估细胞因子诱导的JAK-STAT信号转导途径，该信号转导通路控制MLL和JMJD3的表达并影响后续的免疫反应。我们提出的研究提供了一种创新的方法，通过评估基于表观遗传学的机制来控制与慢性肺部炎症相关的持续炎症表型，并为开发新的生物标记物和新的有效治疗方法提供了机会。

DESCRIPTION (provided by applicant): A lingering conundrum of the immune response is how do certain immune/inflammatory cells "remember" whether or not they should be actively transcribing specific genes, which would facilitate their participation in a given inflammatory response. Our laboratory is investigating novel epigenetic changes, induced via post- translational modifications of histones, as mechanisms to regulate the expression profiles of immune cell derived mediators, during the initiation and maintenance of lung inflammation. We have found that in the presence of either Th1 or Th2 type cytokines dynamic acetylation and/or methylation events occur at the amino terminus of histones H3 and H4, which directly regulate chromatin structures dictating the accessibility of transcription factors to specific promoters. In this application we will utilize established models of lung inflammation, which possess a distinct Th1 or Th2 phenotype, to investigate cytokine-directed, novel epigenetic-based mechanisms that direct the immune cell phenotype in support of lung pathology. Our preliminary data support a key role for epigenetic mechanisms in maintaining the inflammatory phenotype. We hypothesize that during the maintenance of pulmonary disease, a polarized cytokine environment that dictates the phenotype of specific immune cell subpopulations directly induces specific epigenetic changes in the cells, which in turn maintain cell specific transcription program required for disease chronicity. This hypothesis will be investigated via the following specific aims: 1) To investigate cell specific epigenetic changes, which are governed by the dominant cytokine environment associated with a Th1 or a Th2 type pulmonary immune response, 2) To examine the mechanistic role of the histone methyl transferase, MLL, and the histone demethylase, JMJD3, on the development of a Th1 or Th2 dependent pulmonary inflammation using conditional knockout mouse models, and 3) To assess the cytokine-induced JAK-STAT signal transduction pathways that control MLL and JMJD3 expression and influence the subsequent immune response. Our proposed studies provide an innovative approach by assessing the epigenetic-based mechanisms that control the sustained inflammatory phenotype associated with chronic lung inflammation and provide an opportunity for the development of new biomarkers and novel, efficacious therapies.