Differentiation of memory B cells requires EZH2 and epigenetic remodeling

记忆 B 细胞的分化需要 EZH2 和表观遗传重塑

• 批准号: 10680127
• 负责人: Keenan Wiggins
• 金额: $ 4.77万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-23 至 2026-06-22
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680127
• 关键词: 2019-nCoV; Adaptive Immune System; Address; Antigens; B cell differentiation; B cell therapy; B-Cell Activation; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; BACH2 gene; BCL6 gene; Binding; Biological Assay; CCR6 gene; CD4 Positive T Lymphocytes; CD44 gene; CD80 gene; CXCR3 gene; Cell Communication; Cell Cycle Progression; Cell Differentiation process; Cell Reprogramming; Cell Separation; Cell Survival; Cells; Chromatin; Complex; DNA Methylation; DNA Sequence; Development; Enhancers; Environment; Epigenetic Process; Gene Expression; Genes; Genetic Transcription; Histones; Homologous Gene; Humoral Immunities; Immune system; Immunoglobulin-Secreting Cells; Infection; Influenza; Knock-out; Learning; Link; Longevity; Lymphatic System; Maps; Mature B-Lymphocyte; Mediating; Memory B-Lymphocyte; Modification; Molecular; Mus; Nucleosomes; Organism; Pathway interactions; Phenotype; Play; Polycomb; Population; Process; Proteins; Regulation; Research; Resources; Role; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Spleen; Structure of germinal center of lymph node; T-Cell Development; TLR7 gene; Tail; Testing; Untranslated RNA; Vaccination; Vaccines; Work; cell motility; gene repression; histone methyltransferase; histone modification; improved; in vivo; influenzavirus; lymph nodes; migration; mouse model; pathogen; pathogenic bacteria; pathogenic virus; plasma cell differentiation; receptor; recruit; response; transcription factor; transcriptomics; vaccine development

Project Summary: It is important for an organism to develop a strong defense to repel an infection, which means the organism must fine tune its immune system to provide efficient clearance of the pathogen. Reponses to these different pathogens can be further divided to long lasting protection and short-lived protection by B cells 1. In the context of B cell activation, these responses proceed in the lymphatic system in extrafollicular space with the development of Germinal Centers (GC) 5. The use of epigenetics allows us to understand what cellular signals contributes to cellular differentiation after activation and what changes different pathogens create in these responses 36-39. Mouse models are an invaluable resource for studying the immune system. This study aims to define the histone modifications in genes involved in the Memory B Cell (MBC) transcription factor network. We want to know how MBCs differentiate and what differences are there between GC derived and GC-independent MBCs. Some infections are cleared before GCs are made while other infections need the advance fine tenement of B cells for the infection to be cleared 14-16. We will study the phenotypes of MBCs and what effect H3K27 histone modification has on MBC development and function. It has been shown for example that challenging B cells with LPS (type-1 TI antigen) and EZH2 (the protein involved in placing H3K27me3 marks) leads to increased antibody secreting cells 7. We know that MBCs are epigenetically primed at genes involved in B cell activation, signal transduction, survival and migration 28. We aim to uncover what factors support the priming necessary for B cell differentiation in MBCs. This application seeks to test the hypothesis that GC and GC- independent MBCs are a distinct lineage that requires specific molecular signals and epigenetic remodeling. The Specific Aims of this project are: 1: Phenotype MBCs in an PR8 influenza response and 2: Define H3K27me3 role in the development of MBC populations. In Aim 1, we will determine the molecular landscape of MBCs. In Aim 2, we will establish H3K27me3 role in the formation, longevity, and reactivation of MBCs.

项目摘要： 对于有机体而言，重要的是要进行强有力的防御来驱除感染，这意味着 生物体必须微调其免疫系统，以提供病原体的有效清除。 回归这些不同的病原体可以进一步分为持久的保护和 B细胞1。在B细胞激活的背景下，这些反应继续进行 随着生发中心的发展（GC）5的淋巴系统在外毛体空间中。 表观遗传学的使用使我们能够了解哪些细胞信号有助于细胞 激活后的分化以及改变不同病原体在这些反应中产生的变化 36-39。小鼠模型是研究免疫系统的宝贵资源。这项研究 旨在定义涉及记忆B细胞（MBC）的基因中的组蛋白修饰 转录因子网络。我们想知道MBC如何区分和什么差异 GC衍生和与GC无关的MBC之间存在。一些感染之前已清除 在其他感染需要B细胞的预先精细物业时进行GC进行了GC 要清除14-16。我们将研究MBC的表型以及H3K27组蛋白的影响 修改具有MBC的开发和功能。例如，已经显示 具有LPS（1型Ti抗原）和EZH2（与放置有关的蛋白质的蛋白质挑战的B细胞 H3K27me3标记）导致抗体分泌细胞增加7。我们知道MBC是 表观遗传学以B细胞激活，信号转导，存活和 迁移28。我们旨在发现哪些因素支持B细胞所需的启动 MBC的分化。该应用程序旨在检验GC和GC-的假设 独立的MBC是一个独特的谱系，需要特定的分子信号和 表观遗传重塑。该项目的具体目的是：1：PR8中的表型MBC 流感反应和2：定义H3K27ME3在MBC种群发展中的作用。在 AIM 1，我们将确定MBC的分子景观。在AIM 2中，我们将建立 H3K27ME3在MBC的形成，寿命和重新激活中的作用。