Factors and DNA Motifs in Ig Class Switch

摘要 体液免疫依赖于免疫球蛋白(Ig)的表达来抵御 致病挑战。体液免疫系统已经进化到产生免疫球蛋白 广泛的约束性特征曲目。类切换重组(CSR)用于 获得免疫球蛋白效应器功能和组织定位的多样性。小鼠免疫球蛋白常量 5‘-V(D)J-C？-C？3-C？1-C？2B-C？2A-C？-C？-3’。企业社会责任涉及 一种集中在重复区域的染色体内缺失重排 Switch(S)基因位于每个CH基因的上游(C？除外)。这个 企业社会责任的过程可以认为是由三个阶段组成的，包括启蒙、S/S 突触、分解和修复。艾滋病诱导的S地区的DNA损伤启动了 进程。我建议研究导致S/S突触的事件，并辨别染色质 与转录和DNA修复相关的修饰。使用染色体 构象捕获技术(3C)，我的实验室最新研究了长链构象。 位于VH和CH之间的内含子增强子(E)之间的距离相互作用 基因和3‘E？位于免疫球蛋白基因3‘端的增强子与 各种GLT推动者。我们发现在B细胞中，E？和3？E？增强剂即将问世 空间上的接近形成了独特的染色体环构型。B细胞活化 导致生殖系转录本(GLT)启动子被招募到E？复合体 以依赖细胞因子的方式。这一结构促进了S/S的突触，因为S 鄂近区和下游的S区域与目标GLT共同招募 E的启动子：3？很复杂。我们认为GLT启动子与 E？？3？综合体打造建筑脚手架，促进S/S在 CSR和这些相互作用依赖于AID的稳定作用。 染色质重塑是控制可及性的重要调节机制 S的脱氧核糖核酸。我们已经定义了组蛋白修饰，在S和 C区。我们的研究表明染色质的可及性与 组蛋白乙酰化和H3K4me3在S区域，而可及性降低是 与HypoAc和S地区下游的H3K36me3标志有关。我们会 研究这些组蛋白修饰与可及性之间的因果关系。叙事 体液免疫依赖于免疫球蛋白(Ig)的表达来抵御 致病挑战。体液免疫系统已经进化到产生免疫球蛋白 广泛的约束性特征曲目。我们研究分子过程，通过它 表达了新类型的Ig。

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.