Decoding in vivo regulatory programs of CD4+ T lymphocyte populations in inflamma

解码炎症中 CD4 T 淋巴细胞群的体内调节程序

• 批准号: 8991719
• 负责人: Christina S Leslie
• 金额: $ 103.33万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-05 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8991719
• 关键词: Ablation; Architecture; Autoimmune Process; Autoimmunity; Binding; Biological; CD4 Positive T Lymphocytes; Cell model; Cells; ChIP-seq; Chromatin Loop; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Computer Simulation; Control Locus; Coupled; DNA; DNase I hypersensitive sites sequencing; Data; Data Set; Deletion Mutation; Disease; Dissection; Effector Cell; Elements; Enhancers; Epigenetic Process; Exhibits; Experimental Models; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic; Genomics; Health; Histone Deacetylase Inhibitor; Human; Immune; Immune response; Immune system; In Vitro; Individual; Infection; Inflammation; Inflammatory; Injury; Learning; Locus Control Region; Malignant Neoplasms; Maps; Mediating; Metabolic Diseases; Modeling; Mus; Mutate; Neoplasm Metastasis; Organ Transplantation; Organism; Output; Peptide Signal Sequences; Play; Population; Pregnancy; Regulatory Element; Regulatory T-Lymphocyte; Rest; Role; Signal Transduction; Specific qualifier value; Stress; T-Lymphocyte; Tissue-Specific Gene Expression; Transcriptional Activation; bisulfite sequencing; histone modification; in vivo; mouse model; multitask; overexpression; programs; promoter; response; transcriptome sequencing; tumor progression; whole genome

DESCRIPTION (provided by applicant): In multicellular organisms, differentiated cells exhibit specialized functions that are specified by distinct transcriptional and epigenetic programs. Differential use of regulatory elements defines most previously studied lineage specific gene expression programs. However, challenges such as stress, injury, or infection can elicit adaptive or pathogenic responses in differentiated cells leading to a change in their functional state and transcriptional output. Cells of the immune system offer a powerful experimental model for dissection of genomic mechanisms underlying establishment of distinct differentiation and activation states. In this proposal, we study distinct CD4+ T cell populations as they transition from "na�ve" (or resting) to activated states with opposing function: effector T cells that promote - and activated regulatory T cells (Treg) that suppress - immune response and associated inflammation. Resting Treg cells emerge during differentiation as a stable lineage of T lymphocytes distinct from na�ve CD4+ T cells. We will use sophisticated genetic mouse models to generate a short-term inflammatory disorder and investigate genomic features of activated Treg and T effector cells and their resting counterparts in an inflammatory context in vivo. We will profile the enhancer and transcriptional landscapes of the four cell states using DNase-seq, TF and histone modification ChIP-seq, and bulk and single-cell RNA-seq profiles from ex vivo isolated cells. Using these comprehensive data sets, we will: (1) decode the changes in the enhancer landscape that govern the activation of distinct CD4+ T lymphocyte populations; (2) model the differential transcriptional output of genes in these cells as a function of the sequence and activity of their enhancers; and (3) model the expression distribution of individual genes over a population of cells as a function of the state space of their enhancers. Given the central role that Treg cells play in suppressing immune-mediated inflammation in diverse biological contexts ranging from autoimmunity, injury, and infection to pregnancy and metabolic disease as well as emerging understanding of their pivotal role in cancer, our study has broad relevance to human health and major practical significance.

描述（由适用提供）：在多细胞生物中，分化的细胞表现出专门的功能，这些功能由不同的转录和表观遗传程序指定。调节元件的差异使用定义了先前研究的谱系特定基因表达程序。但是，诸如压力，损伤或感染之类的挑战会在分化细胞中引起适应性或致病反应，从而导致其功能状态和转录输出的变化。免疫系统的细胞为解剖基因组机制提供了强大的实验模型，以建立不同的分化和激活状态。在此提案中，我们研究了不同的CD4+ T细胞种群，因为它们从“中殿”（或静止）转变为具有相反功能的激活状态：促进的效应T细胞 - 和激活的调节T细胞（TREG），可抑制免疫响应和相关感染。静止的Treg细胞在分化过程中作为T淋巴细胞的稳定谱系出现，与CD4+ T细胞不同。我们将使用复杂的遗传小鼠模型来产生短期炎症障碍，并研究活化的Treg和T效应细胞的基因组特征及其在体内炎症环境中的静止对应物。我们将使用DNase-Seq，TF和组蛋白修饰的芯片seq以及来自Ex Vivo分离的细胞的大量和单细胞RNA-Seq曲线介绍四个细胞态的增强子和转录景观。使用这些综合数据集，我们将：（1）解码控制不同CD4+ T淋巴细胞种群激活的增强剂景观的变化； （2）模拟这些细胞中基因的差异转录输出作为序列的函数 和增强剂的活动； （3）模拟单个基因在细胞群体中的表达分布与增强子的状态空间的函数。鉴于Treg细胞在抑制免疫介导的感染中起着的主要作用在潜水员生物学环境中，从自身免疫性，损伤和感染到妊娠和代谢疾病，以及对其在癌症中的关键作用的理解，我们的研究与人类健康和主要实际实际意义相关。