Epigenetic Programming of B cell Terminal Differentiation

B 细胞终末分化的表观遗传编程

• 批准号: 8721135
• 负责人: Benjamin Gabriel Barwick
• 金额: $ 4.27万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-21 至 2017-01-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721135
• 关键词: Antibodies; Antigens; Autoimmune Diseases; Autoimmunity; B cell differentiation; B-Cell Activation; B-Lymphocytes; Bacterial Infections; Binding; Binding Sites; Candidate Disease Gene; Cell Cycle; Cell Death; Cell Maintenance; Cell physiology; Cells; Chromatin; DNA; DNA Methylation; Data; Defect; Disease; Disease Outcome; Elements; Enhancers; Enzymes; Epigenetic Process; Epitopes; Flow Cytometry; Gene Expression; Generations; Genes; Genetic; Genetic Models; Genetic Transcription; Genomics; Goals; Hematologic Neoplasms; Hematopoietic; Histocompatibility Antigens Class II; Histones; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunoglobulins; Immunologic Deficiency Syndromes; Individual; Kinetics; Laboratories; Lead; Lymphoid Tissue; Lysine; Maintenance; Measures; Mediating; Methylation; Modification; Molecular; Mono-S; Mus; Parasitic infection; Plasma Cells; Process; Production; Proteins; Publishing; Regulation; Repression; Role; Serum; Signal Transduction; Staining method; Stains; Stimulus; Testing; Transcription Repressor/Corepressor; Vaccination; Vaccine Design; Viral; Virus Diseases; Work; base; chemical addition; chromatin immunoprecipitation; demethylation; differentiated B cell; extracellular; histone modification; immune function; improved; in vivo; insight; plasma cell development; plasma cell differentiation; prevent; programs; public health relevance; receptor; research study; response; transcription factor

DESCRIPTION (provided by applicant): Antibody generation and secretion by B cells provides the basis for humoral immunity. Antibodies bind viral, bacterial and parasitic epitopes facilitatin antigen neutralization and clearance. This immune function results in protective immunity to the host and is exploited to prevent disease by the practice of vaccination. However, very young and old individuals often fail to produce a protective immune response1. Conversely, uncontrolled B cell differentiation can result in hematological malignancy or production of autoreactive antibodies. B cell differentiation is initiated by binding of extracellular stimuli to cellular receptors that trigger a signaling cascade resulting in the induction of transcription factors that reprogram B cells to secrete antibody. Transcription factor function is restricted by the availability of DNA through epigenetic modifications, which are covalent chemical additions to DNA and histones that control the accessibility of chromatin. Epigenetic modifications are heritable through the cell cycle and maintain specific gene expression programs, such as that required to maintain B cell identity. While the epigenetic programming of many hematopoietic processes have been extensively studied2-4, comparatively little work has been conducted to understand the epigenetic mechanisms that govern B cell terminal differentiation into antibody secreting plasma cells. In the following application we propose that epigenetic reprogramming contributes to the humoral immune response. We hypothesize that Lsd1, a histone 3 lysine 4 (H3K4) demethylase, silences the B cell gene expression repertoire by interacting with Blimp1, a key transcription factor in the development of plasma cells. B cell conditional deletion of Lsd1 in mice resulted in diminished plasma cell responses. Genes repressed during B cell differentiation were preferentially enriched for H3K4me1 prior to differentiation and in at least the case of major histocompatibility complex class II (MHCII), were derepressed in Lsd1-deficient plasma cells. These data suggest that Lsd1 epigenetically facilitates reprogramming of B cells into plasma cells. We pose that this is by repression of B cell enhancers, first through demethylation of H3K4me1/2 and subsequently by de novo DNA methylation5,6. We aim to test these hypotheses using genetic models currently in our laboratory in combination with cellular and molecular analyses. The results of these studies will determine the functional and phenotypic impact of Lsd1 in plasma cell formation, reveal Lsd1-induced epigenetic modifications at key B cell genes during plasma cell differentiation, and determine how these epigenetic changes impact the plasma cell gene expression program. Data from this project will illuminate how the humoral immune system is epigenetically reprogrammed in response to antigenic challenge and provide insight into how it can be modulated to improve vaccine design and for the treatment of disease.

描述（由申请方提供）：B细胞产生和分泌抗体为体液免疫提供了基础。抗体结合病毒、细菌和寄生虫表位，促进抗原中和和清除。这种免疫功能导致对宿主的保护性免疫，并通过接种疫苗来预防疾病。然而，非常年轻和年老的个体往往不能产生保护性免疫反应1。相反，不受控制的B细胞分化可导致血液恶性肿瘤或自身反应性抗体的产生。B细胞的分化是通过细胞外刺激物结合到 细胞受体，其触发信号级联，导致诱导转录因子重编程B细胞以分泌抗体。转录因子的功能受到DNA通过表观遗传修饰的可用性的限制，表观遗传修饰是对DNA和组蛋白的共价化学添加，其控制染色质的可及性。表观遗传修饰可通过细胞周期遗传，并维持特定的基因表达程序，例如维持B细胞身份所需的程序。虽然许多造血过程的表观遗传编程已被广泛研究2 -4，但相对较少的工作已被进行以了解控制B细胞终末分化为抗体分泌浆细胞的表观遗传机制。在下面的应用中，我们提出表观遗传重编程有助于体液免疫应答。我们假设Lsd 1是一种组蛋白3赖氨酸4（H3 K4）脱甲基酶，通过与浆细胞发育中的关键转录因子Blimp 1相互作用，沉默B细胞基因表达谱。小鼠中Lsd 1的B细胞条件性缺失导致浆细胞反应减弱。在B细胞分化过程中抑制的基因在分化前优先富集H3 K4 me 1，并且至少在主要组织相容性复合体II类（MHCII）的情况下，在Lsd 1缺陷型浆细胞中被去抑制。这些数据表明，Lsd 1表观遗传学上有利于将B细胞重编程为浆细胞。我们认为这是通过抑制B细胞增强子，首先通过H3 K4 me 1/2的去甲基化，随后通过从头DNA甲基化5，6。我们的目标是使用我们实验室目前的遗传模型结合细胞和分子分析来测试这些假设。这些研究的结果将确定Lsd 1在浆细胞形成中的功能和表型影响，揭示浆细胞分化过程中Lsd 1诱导的关键B细胞基因的表观遗传修饰，并确定这些表观遗传变化如何影响浆细胞基因表达程序。该项目的数据将阐明体液免疫系统如何在表观遗传学上重新编程以应对抗原挑战，并提供如何调节以改善疫苗设计和治疗疾病的见解。