Role of the developmental regulator Gon4-like in B lymphopoiesis

发育调节因子 Gon4 样在 B 淋巴细胞生成中的作用

• 批准号: 8584228
• 负责人: JOHN D COLGAN
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-02 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8584228
• 关键词: Affect; Antibodies; Appearance; B-Cell Development; B-Lymphocytes; Biochemical; Blood; Bone Marrow; CCAAT-Enhancer-Binding Proteins; Cancer Biology; Cell Culture System; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Complement; Complex; DNA Repair; DNA-Binding Proteins; Data; Development; Disease; Epigenetic Process; Event; Gene Activation; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Gene Targeting; Gene Transfer; Generations; Genes; Genetic; Genetic Recombination; Genetic Transcription; Hematopoietic; Human; Immune System Diseases; Immune system; Immunity; Immunoglobulin Gene Rearrangement; Immunoglobulin Genes; Immunologic Deficiency Syndromes; Impairment; Infection; Knowledge; Lead; Lesion; Libraries; Life; Link; Lymphocyte; Lymphoid; Lymphopoiesis; Malignant Neoplasms; Mature B-Lymphocyte; Mediating; Methods; Molecular; Multipotent Stem Cells; Mus; Mutant Strains Mice; Mutation; Myelogenous; Myeloid Cells; Names; Neoplasms; Pathway interactions; Physiological; Physiology; Point Mutation; Process; Proteins; Regulation; Research; Role; Series; Signal Transduction; Source; Staging; Stem cells; Supporting Cell; T-Lymphocyte; TCF3 gene; Technology; Testing; Transplantation; Work; base; cell growth; cell type; fighting; gene repression; genome-wide; imprint; insight; leukemia; mouse development; novel; prevent; progenitor; programs; protein function; research study; response; tool; transcription factor

DESCRIPTION (provided by applicant): B cells represent a critical component of the immune system: in the absence of these cells, the ability to fight infections and to establish long-term protective immunity are severely impaired. B cell development and function depend on elaborate mechanisms that tightly control gene expression and the physiologic breakage and repair of DNA that occurs uniquely in lymphoid progenitors. Although these mechanisms function with remarkable fidelity, they can be perturbed by discrete genetic lesions, leading to immune dysfunction or lymphocytic cancers in humans. Thus, dissecting the molecular pathways that control B cell development is critical to advancing our understanding of normal immune system physiology and diseases that arise from the B cell compartment. The overarching objective of our proposal is to gain new insight into the mechanisms that globally control gene expression during B cell development. It has been established that a regulatory network anchored by several DNA-binding proteins is primarily responsible for controlling gene transcription during B cell development. This network enforces widespread gene repression as well as activation, thus imparting a B- lineage identity onto developing progenitors. Yet, the factors that function downstream of B-lineage DNA- binding proteins to globally orchestrate gene repression and activation have only begun to be identified. In our previous studies, we identified a novel mutant mouse strain named Justy (for just T cells), which carries a recessive mutation that abolishes B cell development but does not impair other major aspects of mouse physiology. The causative lesion is a point mutation that dramatically reduces, but does not abolish, expression of a protein called Gon4-like, which contains homology to factors that mediate epigenetic regulation of gene transcription. Gene expression profiling indicated that decreased Gon4-like expression does not impair activation of B-lineage genes, but does prevent the repression of genes encoding proteins that can antagonize B cell development. Among these are genes encoding factors that have lineage-instructive roles in hematopoietic developmental pathways. Based on these data, we hypothesize that Gon4-like is a critical component of the regulatory network that establishes a B-lineage gene program identity while extinguishing alternative lineage programs, particularly those associated with myeloid cell development. We propose to employ mouse genetic tools, cell culture systems, retroviral gene transfer technology and methods for quantifying gene expression to carry out studies that will integrate Gon4-like into the regulatory circuitry the controls B cell development. To complement these studies, we will use molecular and biochemical approaches to identify co-factors for Gon4-like and to begin defining the role of Gon4-like in gene regulation on a genome-wide scale. Completion of these studies will break new ground in our understanding of the mechanisms that control hematopoietic lineage fate decisions and imprint commitment to a B cell fate. Such knowledge will provide novel insights regarding the relationships between impairment of B cell development and the appearance of immunodeficiencies or B cell progenitor-derived lymphoid cancers.

描述（由申请人提供）：B 细胞代表免疫系统的关键组成部分：如果缺乏这些细胞，抵抗感染和建立长期保护性免疫的能力就会严重受损。 B 细胞的发育和功能取决于严格控制基因表达以及淋巴祖细胞中独特发生的 DNA 生理断裂和修复的复杂机制。尽管这些机制以惊人的保真度发挥作用，但它们可能会受到离散遗传病变的干扰，导致人类免疫功能障碍或淋巴细胞癌症。因此，剖析控制 B 细胞发育的分子途径对于增进我们对正常免疫系统生理学和 B 细胞区室引起的疾病的理解至关重要。 我们提案的首要目标是获得对 B 细胞发育过程中全局控制基因表达的机制的新见解。已经确定，由几种 DNA 结合蛋白锚定的调控网络主要负责控制 B 细胞发育过程中的基因转录。该网络强制执行广泛的基因抑制和激活，从而将 B 谱系身份赋予正在发育的祖细胞。然而，在 B 谱系 DNA 结合蛋白下游发挥作用以全局协调基因抑制和激活的因子才刚刚开始被识别。在我们之前的研究中，我们发现了一种名为 Justy（仅针对 T 细胞）的新型突变小鼠品系，它携带隐性突变，该突变会废除 B 细胞发育，但不会损害小鼠生理学的其他主要方面。致病病变是一种点突变，它会显着减少但不会消除一种名为 Gon4 样蛋白的表达，该蛋白与介导基因转录表观遗传调控的因子具有同源性。基因表达谱表明，Gon4 样表达的减少不会损害 B 谱系基因的激活，但确实会阻止编码可拮抗 B 细胞发育的蛋白质的基因受到抑制。其中包括编码在造血发育途径中具有谱系指导作用的因子的基因。基于这些数据，我们假设 Gon4 样是调节网络的关键组成部分，该网络建立 B 谱系基因程序身份，同时消除替代谱系程序，特别是与骨髓细胞发育相关的谱系程序。我们建议采用小鼠遗传工具、细胞培养系统、逆转录病毒基因转移技术和定量基因表达的方法来开展研究，将 Gon4 样整合到控制 B 细胞发育的调节电路中。为了补充这些研究，我们将使用分子和生化方法来识别 Gon4 样的辅助因子，并开始定义 Gon4 样在全基因组范围内的基因调控中的作用。这些研究的完成将为我们理解控制造血谱系命运决定和印记 B 细胞命运的机制开辟新的领域。这些知识将为 B 细胞发育受损与免疫缺陷或 B 细胞祖源性淋巴癌的出现之间的关系提供新的见解。