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.

项目总结: