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Factors and DNA Motifs in Ig Class Switch

Ig 类别转换中的因素和 DNA 基序

基本信息

批准号：
8278633
负责人：
Amy L Kenter
金额：
$ 43.85万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8278633
关键词：
Attention B-Cell Activation B-Lymphocytes Binding Chromatin Chromosomal translocation Chromosome Pairing Chromosomes Complex DNA DNA Repair DNA Sequence Rearrangement DNA lesion DNA repair protein Dominant-Negative Mutation EP300 gene Ectopic Expression Enhancers Equilibrium Event Exclusion Genes Genetic Genetic Recombination Genetic Transcription Histone Acetylation Histone Deacetylase Inhibitor Histone H4 Histones Homologous Gene Humoral Immunities IGH@ gene cluster Immune system Immunoglobulin Class Switching Immunoglobulin Constant Region Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Immunoglobulins Investigation Laboratories Lead Methods Modification Molecular Molecular Conformation Mus Mutation Oncogenic Phase Preparation Process Proteins Recruitment Activity Regulatory Element Repetitive Sequence Resolution Role Site Specificity Structure Synapses Synaptosomes T-Lymphocyte Techniques Testing Tissues Transcript activation-induced cytidine deaminase chromatin modification chromatin remodeling complement C2a cytokine histone modification in vivo novel promoter repaired scaffold

项目摘要

ABSTRACT Humoral immunity is dependent on the expression of immunoglobulin (Ig) to fend off pathogenic challenges. The humoral immune system has evolved to produce Ig with a broad repertoire of binding specificities. Class switch recombination (CSR) is used to attain diversity of Ig effector function and tissue localization. The murine IgH constant region locus is organized: 5'-V(D)J-C¿-C?-C?3-C?1-C?2b-C?2a-C?-C?-3'. CSR involves an intra-chromosomal deletional rearrangement that focuses on regions of repetitive switch (S) DNA located upstream of each CH gene (with the exception of C?). The process of CSR can be thought of as composed of three phases including, initiation, S/S synapsis and resolution and repair. AID induced DNA lesions at S regions initiates the process. I propose to examine events leading to S/S synapsis, and discern chromatin modifications associated with transcription and DNA repair. Using the chromosome conformation capture technique (3C), my laboratory has newly investigated the long- range interactions between the ¿ intronic enhancer (E¿) located between the VH and CH genes and the 3'E? enhancer located at the 3'-end of the IgH locus together with the various GLT promoters. We find that in B cells, the E¿ and 3¿E? enhancers are in close spatial proximity forming an unique chromosomal loop configuration. B cell activation leads to recruitment of the germline transcript (GLT) promoters to the E¿:3¿E? complex in a cytokine dependent fashion. This structure facilitates S/S synapsis since S¿ is proximal to E¿ and the downstream S region are co-recruited with the targeted GLT promoter to the E¿:3¿E? complex. We propose that GLT promoter association with the E¿:3¿E? complex creates an architectural scaffolding that promotes S/S synapsis during CSR and these interactions are dependent on the stabilizing influence of AID. Chromatin remodeling is an important regulatory mechanism controlling the accessibility of S DNA to AID. We have defined histone modifications differentially found in the S and C regions. Our studies indicate chromatin accessibility is correlated with increased histone acetylation and H3K4me3 at the S regions whereas reduced accessibility is associated with hypoAc and the H3K36me3 mark downstream of the S region. We will study the causual relationship between accessibility and these histone modification. NARRATIVE Humoral immunity is dependent on the expression of immunoglobulin (Ig) to fend off pathogenic challenges. The humoral immune system has evolved to produce Ig with a broad repertoire of binding specificities. We study the molecular processes by which new types of Ig are expressed.

摘要体液免疫是依靠免疫球蛋白（IG）的表达来抵御病原挑战体液免疫系统已经进化到产生IG，广泛的结合特异性库。类别切换重组（CSR）用于获得IG效应子功能和组织定位的多样性。鼠IgH常数区域基因座组织为：5 '-V（D）J-C <$-C？- C？3-C 1-C？2b-C？2a-C C？3'. CSR涉及一种染色体内缺失重排，集中在重复区域，位于每个CH基因上游的开关（S）DNA（C？除外）。的企业社会责任的过程可分为三个阶段，即启动阶段、S/S阶段突触、分解和修复。艾滋病诱导的DNA损伤在S区启动过程我建议检查导致S/S突触的事件，与转录和DNA修复相关的修饰。利用染色体构象捕获技术（3C），我的实验室最近研究了长- 位于VH和CH之间的<$内含子增强子（E <$）之间的范围相互作用基因和3 'E？位于IgH基因座的3 '端的增强子与各种GLT启动子。我们发现，在B细胞中，E和3 E？增强剂在接近空间接近形成独特的染色体环构型。B细胞活化导致生殖系转录本（GLT）启动子的E：3 E？复杂以细胞因子依赖的方式。这种结构有利于S/S突触，因为S是 E区近端和下游S区与靶向GLT共同募集 #36825;的启动子：3？复杂.我们认为GLT启动子与 E：3 E？复合体创造了一个建筑脚手架，促进S/S突触，企业社会责任和这些相互作用取决于援助的稳定影响。染色质重塑是控制细胞可及性的重要调控机制 S DNA到艾滋病。我们已经定义了在S和S中发现的差异性组蛋白修饰， C区。我们的研究表明，染色质可及性与增加组蛋白乙酰化和H3 K4 me 3在S区，而减少的可及性，与S区下游的hypoAc和H3 K36 me 3标记相关。我们将研究可及性与这些组蛋白修饰之间的因果关系。叙事体液免疫是依靠免疫球蛋白（IG）的表达来抵御病原挑战体液免疫系统已经进化到产生IG，广泛的结合特异性库。我们研究的是表达了新型的IG。