Cytokine-induced epigenetic changes during chronic lung disease

描述（由申请人提供）：免疫应答的一个挥之不去的难题是某些免疫/炎症细胞如何“记住”它们是否应该积极转录特定基因，这将促进它们参与给定的炎症应答。我们的实验室正在研究通过组蛋白的翻译后修饰诱导的新型表观遗传变化，作为在肺部炎症的起始和维持期间调节免疫细胞衍生的介质的表达谱的机制。我们已经发现，在Th 1或Th 2型细胞因子的存在下，动态乙酰化和/或甲基化事件发生在组蛋白H3和H4的氨基末端，其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 在本申请中，我们将利用已建立的具有不同Th 1或Th 2表型的肺部炎症模型来研究指导免疫细胞表型以支持肺部病理学的、基于表观遗传学的新的、由精氨酸指导的机制。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中的特定表观遗传变化，这反过来又维持疾病慢性化所需的细胞特异性转录程序。将通过以下具体目标对这一假设进行研究：1）研究细胞特异性表观遗传变化，其由与Th 1或Th 2型肺免疫应答相关的显性细胞因子环境控制，2）检查组蛋白甲基转移酶MLL和组蛋白脱甲基酶JMJD 3的机制作用，使用条件性基因敲除小鼠模型对Th 1或Th 2依赖性肺部炎症的发展的影响，以及3）评估控制MLL和JMJD 3表达并影响随后的免疫应答的奎宁诱导的JAK-STAT信号转导途径。我们提出的研究通过评估控制与慢性肺部炎症相关的持续炎症表型的基于表观遗传的机制提供了一种创新方法，并为开发新的生物标志物和新型有效疗法提供了机会。

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.