An experimentally-refined, dynamic gene regulatory network model of T-cell memory

经过实验改进的 T 细胞记忆动态基因调控网络模型

• 批准号: 10213550
• 负责人: Artem Barski
• 金额: $ 44.56万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2021-03-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213550
• 关键词: 3-Dimensional; Address; Allergic; Antigen-Presenting Cells; Antigens; Asthma; Autoimmune Process; Autoimmunity; Automobile Driving; Binding; Binding Sites; Cell Nucleus; Cell Proliferation; Cells; Characteristics; Chromatin; Clonal Expansion; Collaborations; Computing Methodologies; Cytokine Gene; Cytokine Signaling; DNA; Data; Disease; Engineering; Enhancers; Epigenetic Process; Event; Exposure to; Family; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genomics; Health; Homeostasis; Human; Hypersensitivity; Immune; Immune response; Immunity; Immunologic Memory; Individual; Infection; Inflammatory; Knowledge; Lead; Longevity; Malignant Neoplasms; Maps; Mathematics; Measurement; Mediating; Memory; Minor; Modeling; Molecular; Molecular Conformation; Nuclear Translocation; Pathologic; Population; Regulator Genes; Regulatory Element; Research Design; Resources; Rest; Role; SP1 gene; Signal Transduction; Site; System; T memory cell; T-Cell Activation; T-Lymphocyte; Transcription Factor AP-1; Tumor Immunity; Vaccination; Vaccines; adaptive immunity; anti-cancer; chromatin modification; chromatin remodeling; computer studies; cytokine; epigenetic regulation; epigenome; experimental study; fighting; genome-wide; improved; mathematical model; network models; new technology; novel; novel therapeutics; pathogen; pathogen exposure; promoter; rapid technique; response; risk variant; single-cell RNA sequencing; transcription factor

An experimentally-refined, dynamic gene regulatory network model of T-cell memory Summary T cell memory induced by prior exposure to a pathogen or vaccination provides enhanced protection against a subsequent infection with the same pathogen. Enhanced protection is partially driven by clonal expansion, which leads to an increased number of T cells capable of recognizing the antigen. Additionally, memory T cells possess a “rapid recall ability” that allows them to fight pathogens by producing cytokines and other effector molecules within minutes of re-exposure (as opposed to days, upon initial exposure). We recently showed that the rapid recall ability correlates with the epigenetic poising of enhancers and promoters of the “rapid-recall genes” in memory T cells. Importantly, the sites of epigenetic change significantly overlap with the risk loci for autoimmune and atopic disease, suggesting that this mechanism is important for immune homeostasis. However, it is still unclear if and how the epigenetic poising causes enhanced expression of rapid recall genes. Furthermore, memory T cells persist for a lifetime; yet the mechanisms that maintain the memory epigenome – for decades in the absence of antigen – are not known. Our preliminary data suggest that rapid recall is coordinated by several families of transcription factors (TFs) and thousands of putative DNA regulatory elements. This complexity requires a systems-level, engineering approach. Thus, this proposal is a collaboration between the groups of Artem Barski, a T cell biologist, and Emily Miraldi, a mathematical modeler, to create an experimentally validated, genome-scale model of memory immune response. Aim 1. Using single-cell genomics, we will characterize the gene expression and chromatin dynamics of T cell activation in naïve and memory cells and build mathematical models that integrate these data (along with relevant existing genomics resources) into a dynamic gene regulatory network (GRN). Our GRN model will predict the molecular drivers (TFs) and regulatory elements that orchestrate rapid recall. Aim 2. Although T-cell activation in naïve and memory cells similarly promotes nuclear translocation of inducible TFs, our data lead us to hypothesize that chromatin remodeling upon initial pathogen exposure alters the occupancy of inducible TFs in memory T cells and that this is the basis of rapid recall. We will combine dynamic TF perturbation and occupancy experiments to establish the molecular interactions driving rapid recall. Aim 3. We will identify the mechanisms by which memory T cells maintain the epigenome conducive for rapid recall – over the human lifespan. We hypothesize that constitutive TFs maintain the epigenome poised for rapid recall. We propose dynamic TF perturbation experiments to uncover the identities of these regulators. This study will help uncover basic mechanisms of T cell memory and identify potential targets for manipulating immunologic memory responses. Because rapid recall is the basis for vaccination and central to allergy, asthma, and cancer immunity, this study will have a broad impact on human health.

经过实验改进的 T 细胞记忆动态基因调控网络模型 概括 先前接触病原体或接种疫苗所诱导的 T 细胞记忆可提供针对病原体的增强保护 随后感染相同的病原体。增强的保护部分是由克隆扩展驱动的，这 导致能够识别抗原的 T 细胞数量增加。此外，记忆T细胞还具有 “快速回忆能力”使它们能够通过产生细胞因子和其他效应分子来对抗病原体 重新暴露后几分钟内（而不是初次暴露后几天）。我们最近表明，快速 回忆能力与“快速回忆基因”的增强子和启动子的表观遗传平衡相关 记忆T细胞。重要的是，表观遗传变化的位点与风险位点显着重叠。 自身免疫性和特应性疾病，表明这种机制对于免疫稳态很重要。 然而，目前尚不清楚表观遗传平衡是否以及如何导致快速回忆基因表达增强。 此外，记忆T细胞会持续一生；然而维持记忆表观基因组的机制—— 几十年来在没有抗原的情况下——尚不清楚。我们的初步数据表明，快速回忆是 由几个转录因子 (TF) 家族和数千个假定的 DNA 调控协调 元素。这种复杂性需要系统级的工程方法。因此，本提案是一项合作 T 细胞生物学家 Artem Barski 和数学建模师 Emily Miraldi 的团队合作，创建了一个 经过实验验证的记忆免疫反应的基因组规模模型。 目标 1. 利用单细胞基因组学，我们将表征 T 细胞的基因表达和染色质动态 激活幼稚细胞和记忆细胞，并建立整合这些数据的数学模型（以及 相关的现有基因组学资源）整合到动态基因调控网络（GRN）中。我们的 GRN 模型将 预测协调快速回忆的分子驱动因素（TF）和调节元件。 目标 2. 尽管幼稚细胞和记忆细胞中的 T 细胞激活同样会促进 诱导型转录因子，我们的数据使我们推测染色质重塑在初始病原体暴露时会改变 记忆 T 细胞中诱导型转录因子的占据，这是快速回忆的基础。我们将结合 动态 TF 扰动和占用实验，以确定驱动快速回忆的分子相互作用。 目标 3. 我们将确定记忆 T 细胞维持有利于记忆的表观基因组的机制 快速回忆——在人类的一生中。我们假设组成型转录因子维持表观基因组的状态 快速回忆。我们提出动态 TF 扰动实验来揭示这些调节器的身份。 这项研究将有助于揭示 T 细胞记忆的基本机制，并确定 T 细胞记忆的潜在靶点。 操纵免疫记忆反应。因为快速回忆是疫苗接种的基础，也是疫苗接种的核心 过敏、哮喘和癌症免疫，这项研究将对人类健康产生广泛影响。