Regulation of chromatin modifications by miRNAs to control cytokine expression

通过 miRNA 调节染色质修饰来控制细胞因子表达

• 批准号: 8440676
• 负责人: To-Ha Thai
• 金额: $ 43.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440676
• 关键词: 3' Untranslated Regions; Acute; Antibody Formation; Antigen Receptors; Biology; CD4 Positive T Lymphocytes; Cancer Biology; Cells; ChIP-seq; Chromatin; Chromatin Structure; Chronic Disease; Complex; Coronary Arteriosclerosis; Cytokine Gene; Data; Development; Diabetes Mellitus; Discipline; Disease; Drug Design; Effector Cell; Epigenetic Process; Future; Gene Expression; Gene Expression Profile; Generations; Genetic; Genetic Transcription; Histones; Human; Immune; Immune response; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-17; Knowledge; Link; Lymphocyte; Malignant Neoplasms; Maps; Mediating; Memory; MicroRNAs; Modification; Molecular; Multiple Sclerosis; Mutant Strains Mice; Nuclear; Obesity; Outcome; Pathology; Pathway interactions; Phosphorylation; Process; Production; Reaction; Receptor Activation; Regulation; Regulator Genes; Role; STAT3 gene; Scientist; Spondylarthropathies; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte; Therapeutic Agents; Transgenic Organisms; chromatin modification; chromatin remodeling; cytokine; design; gene function; histone modification; immune function; improved; in vivo; innovation; interleukin-22; mouse model; mutant; mutant mouse model; novel; overexpression; pathogen; programs; response; tool; transcription factor

DESCRIPTION (provided by applicant): Dysregulated generation of effector cells and their cytokines often results in the development of inflammatory- related diseases such as diabetes, inflammatory bowel disease, multiple sclerosis, the spondyloarthropathies and systemic lupus erythematosus (SLE). Inappropriate responses to cytokines following antigen receptor activation during acute infections can skew lymphocyte development toward memory versus effector cells resulting in an inability to resolve infections. To further our understanding of underlying disease mechanisms mediated by cytokines and to generate new and improved therapies, it will be necessary to continue to dissect how cytokine gene expression and function are regulated during an inflammatory response. Recently we have shown that miRNAs have a significant impact on immune system functions. Specifically, miR-155 exerts its control on the immune response this control, in part, by regulating cytokine production. However, the molecular mechanisms by which miR-155 controls cytokine production have not been fully appreciated. Using our miR- 155 mutant mouse model, we believe our preliminary data offers the first evidence that miRNAs control the expression of specific inflammatory cytokines by controlling chromatin remodeling. We show: 1) miR-155 regulates the production of specific effector cytokines, including IL-17 and IL-22, but not IL-17F or IL-21 both of which also define the TH-17 lineage and function; 2) neither il-17 nor il-22 3' untranslated regions (UTR) contain predicted miR-155 target sequences, and miR-155 controls IL-17 and IL-22 production through a pathway distinct from the STAT3 and ROR¿t/ROR¿ transcriptional pathways; 3) mechanistically, we have demonstrated that the expression and phosphorylation status of the histone modifier HP-1¿ are compromised in miR-155-/- TH-17 cells, and by correcting the level of HP-1¿ in the mutant cells we could partially rescue the defective TH-17 cytokine expression program. More importantly, these observations were confirmed in human TH-17 cells. Hence, the following aims form the core of our proposal: 1) Determine how does HP-1¿ regulate TH-17 cytokine gene expression 2) Determine the impact HP-1¿ has on global gene expression during CD4+ T cell activation/differentiation. 3) Study the regulatory effects of HP-1¿ on immune functions and gene expression in vivo. These studies will provide the first and comprehensive understanding of the novel role of miRNAs such as miR-155 in the function of the epigenetic modifier HP-1¿ in immune cells, and the impact this control has on inflammatory cytokine gene expression as well as global gene expression. They will reveal the previously unknown regulatory mechanism of IL-17 and IL-22 gene expression that is distinct from the accepted paradigm. They will define the immunological impact of one miRNA, from epigenetic regulation of global lymphocyte gene expression to broader effects on immune pathologies, thus aiding in future drug design efforts targeting miRNAs.

描述（由申请人提供）：效应细胞及其细胞因子的生成失调通常会导致炎症相关疾病的发生，例如糖尿病、炎症性肠病、多发性硬化症、脊柱关节病和系统性红斑狼疮（SLE）。急性感染期间抗原受体激活可能会使淋巴细胞向记忆细胞和效应细胞方向发展，从而导致无法解决感染问题。 为了研究细胞因子介导的机制并产生新的和改进的疗法，有必要继续剖析炎症反应期间细胞因子基因表达和功能的调节方式。 miR-155 部分地通过调节细胞因子的产生来发挥其对免疫反应的控制作用。然而，使用我们的 miR-155 突变小鼠尚未完全了解 miR-155 控制细胞因子产生的分子机制。模型中，我们相信我们的初步数据提供了第一个证据，证明 miRNA 通过控制染色质重塑来控制特定炎症细胞因子的表达，我们表明：1) miR-155 调节特定效应细胞因子的产生，包括 IL-17 和 IL-22，但不包括 IL-17F 或 IL-21，它们也定义了 TH-17 谱系和功能 2) 既不是 il-17 也不是 il-22 3' 非翻译区； (UTR) 包含预测的 miR-155 靶序列，并且 miR-155 通过与 STAT3 和 ROR 不同的途径控制 IL-17 和 IL-22 的产生t/ROR¿转录途径；3) 从机制上讲，我们已经证明组蛋白修饰剂 HP-1¿在 miR-155-/- TH-17 细胞中受到损害，并通过纠正 HP-1 的水平在突变细胞中，我们可以部分挽救有缺陷的 TH-17 细胞因子表达程序。更重要的是，这些观察结果在人类 TH-17 细胞中得到了证实。因此，以下目标构成了我们建议的核心：1) 确定 HP-如何发挥作用。 1??调节 TH-17 细胞因子基因表达 2) 确定 HP-1¿对 CD4+ T 细胞激活/分化过程中的全局基因表达具有影响 3) 研究 HP-1¿这些研究将首次全面了解 miRNA（例如 miR-155）在表观遗传修饰剂 HP-1 功能中的新作用。他们将揭示以前未知的 IL-17 和 IL-22 基因表达的调节机制，这与公认的范式不同。一种 miRNA 的免疫学影响，从全局淋巴细胞基因表达的表观遗传调控到对免疫病理学的更广泛影响，从而有助于未来针对 miRNA 的药物设计工作。

项目成果

HP-1γ Controls High-Affinity Antibody Response to T-Dependent Antigens.

HP-1γ 控制对 T 依赖性抗原的高亲和力抗体反应。

• 发表时间: 2014
• 作者: Ha, Ngoc;Pham, Duc;Shahsafaei, Aliakbar;Naruse, Chie;Asano, Masahide;Thai, To
• 通讯作者: Thai, To

The State of Cellular Adoptive Immunotherapy for Neuroblastoma and Other Pediatric Solid Tumors.

神经母细胞瘤和其他儿科实体瘤的细胞过继免疫疗法的现状。

• 发表时间: 2017
• 作者: Le, Thanh;Thai, To
• 通讯作者: Thai, To