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: 10210685
• 负责人: Artem Barski
• 金额: $ 53.75万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-08 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10210685
• 关键词: 3-Dimensional; Address; Allergic; Antigen-Presenting Cells; Antigens; Asthma; Autoimmune; 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; Genomics; Health; Human; Hypersensitivity; Immune; Immune response; Immunity; Immunologic Memory; Individual; Infection; Inflammatory; Knowledge; Lead; Longevity; Maintenance; 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; anti-cancer; chromatin modification; chromatin remodeling; computer studies; cytokine; epigenetic regulation; epigenome; experimental study; fighting; genome-wide; improved; insight; mathematical model; network models; new technology; novel; 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 rapid recall 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 human health. 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– 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 experimentally validated, genome-scale models of memory immune responses across heterogeneous T cell populations. 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.

T细胞记忆的实验精制，动态基因调节网络模型 概括 事先暴露于病原体或疫苗接种引起的T细胞记忆提供了增强的保护 随后感染相同的病原体。加强保护部分是由克隆扩张驱动的， 导致能够识别抗原的T细胞数量增加。此外，内存T细胞还具有 “快速召回能力”，使他们能够通过产生细胞因子和其他效应分子来抗击病原体 在重新曝光的几分钟内（与初次接触时几天相对）。我们最近证明了快速召回 与记忆T细胞中“快速回调基因”的增强子和启动子的表观遗传中毒相关。 重要的是，表观遗传变化的地点与自身免疫性和特征性的风险基因座显着重叠 疾病，表明这种机制对人类健康很重要。但是，仍然不清楚是否以及如何 表观中毒导致快速回忆基因的表达增强。此外，记忆T细胞持续存在 一生然而，数十年来维持记忆表观基因组的机制尚不清楚。我们的 初步数据表明，快速召回是由几个转录因子（TF）和 数千个推定的DNA调节元件。这种复杂性需要一种系统级的工程方法。 这是该提议是T细胞生物学家Artem Barski和Emily Miraldi的合作 数学建模器，用于创建经过实验验证的内存免疫反应的基因组规模模型 跨越异质的T细胞群体。 AIM 1。使用单细胞基因组学，我们将表征T细胞的基因表达和染色质动力学 在幼稚和记忆单元中激活并构建整合这些数据的数学模型（以及 相关的现有基因组资源）进入动态基因调节网络（GRN）。我们的GRN模型将 预测协调快速召回的分子驱动因素（TFS）和调节元素。 目标2.尽管幼稚和记忆细胞中的T细胞激活类似地促进 诱导TFS，我们的数据使我们假设在初始病原体暴露时进行染色质重塑改变了 记忆T细胞中诱导型TF的占用率，这是快速召回的基础。我们将结合 动态TF扰动和占用实验，以建立推动快速回忆的分子相互作用。 AIM 3。我们将确定记忆T细胞维持表观基因组导电的机制 快速召回 - 在人类的寿命上。我们假设本构型TF保持了中毒的表观基因组 快速召回。我们提出动态TF扰动实验，以发现这些调节剂的身份。 这项研究将有助于发现T细胞记忆的基本机制，并确定潜在的目标 操纵免疫记忆反应。因为快速召回是疫苗接种的基础，而是核心 过敏，哮喘和癌症免疫学，这项研究将对人类健康产生广泛的影响。