Differentiation of memory B cells requires EZH2 and epigenetic remodeling

项目摘要： 对于生物体来说，重要的是发展强大的防御来抵御感染，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。 对这些不同病原体的反应可以进一步分为长期持久的保护和 B细胞的短期保护1.在B细胞活化的情况下，这些反应在 淋巴系统在滤泡外空间与发展的Germinus中心（GC）5。 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 以及不同病原体在这些反应中产生了什么样的变化 36-39.小鼠模型是研究免疫系统的宝贵资源。本研究 目的是确定记忆B细胞（MBC）中相关基因的组蛋白修饰 转录因子网络我们想知道MBC如何区分，以及有哪些差异 GC衍生的MBC和GC非依赖性MBC之间存在差异。有些感染在 当其他感染需要B细胞的高级细链进行感染时，GC被制造出来 14-16号可以通过我们将研究MBCs的表型以及H3 K27组蛋白对MBCs的表型的影响。 改性对MBC的发展和功能的影响。例如，已经证明， 用LPS（1型TI抗原）和EZH 2（参与放置的蛋白质）攻击B细胞 H3 K27 me 3标记）导致抗体分泌细胞增加7.我们知道MBC是 表观遗传学上启动了参与B细胞活化、信号转导、存活和 移徙28.我们的目标是揭示哪些因素支持B细胞启动所必需的 MBC的差异化。本申请试图测试GC和GC- 独立的MBC是需要特定分子信号的独特谱系， 表观遗传重塑本项目的具体目的是：1：PR 8中的表型MBC 流感反应和2：定义H3 K27 me 3在MBC人群发展中的作用。在 目的1，我们将确定MBCs的分子景观。在目标2中，我们将建立 H3 K27 me 3在MBC的形成、寿命和再活化中的作用

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.