UMR CNRS 6101, Centre National de la Recherche Scientifique, Université de Limoges, Limoges, France.
Adv Immunol. 2011;110:27-70. doi: 10.1016/B978-0-12-387663-8.00002-8.
Antigen receptor gene loci are among the most complex in mammals. The IgH locus, encoding the immunoglobulin heavy chain (IgH) in B-lineage cells, undergoes major transcription-dependent DNA remodeling events, namely V(D)J recombination, Ig class-switch recombination (CSR), and somatic hypermutation (SHM). Various cis-regulatory elements (encompassing promoters, enhancers, and chromatin insulators) recruit multiple nuclear factors in order to ensure IgH locus regulation by tightly orchestrated physical and/or functional interactions. Among major IgH cis-acting regions, the large 3' regulatory region (3'RR) located at the 3' boundary of the locus includes several enhancers and harbors an intriguing quasi-palindromic structure. In this review, we report progress insights made over the past decade in order to describe in more details the structure and functions of IgH 3'RRs in mouse and human. Generation of multiple cellular, transgenic and knock-out models helped out to decipher the function of the IgH 3' regulatory elements in the context of normal and pathologic B cells. Beside its interest in physiology, the challenge of elucidating the locus-wide cross talk between distant cis-regulatory elements might provide useful insights into the mechanisms that mediate oncogene deregulation after chromosomal translocations onto the IgH locus.
抗原受体基因座是哺乳动物中最复杂的基因座之一。编码 B 细胞系免疫球蛋白重链 (IgH) 的 IgH 基因座经历主要的转录依赖性 DNA 重塑事件，即 V(D)J 重组、Ig 类别转换重组 (CSR) 和体细胞高频突变 (SHM)。各种顺式调控元件（包括启动子、增强子和染色质绝缘子）招募多个核因子，以确保 IgH 基因座的调节通过紧密协调的物理和/或功能相互作用。在主要的 IgH 顺式作用区域中，位于基因座 3' 边界的大型 3' 调控区 (3'RR) 包含几个增强子，并具有一个有趣的准回文结构。在这篇综述中，我们报告了过去十年取得的进展，以便更详细地描述小鼠和人类 IgH 3'RR 的结构和功能。多种细胞、转基因和敲除模型的产生有助于阐明 IgH 3' 调控元件在正常和病理 B 细胞中的功能。除了在生理学上的意义外，阐明远距离顺式调控元件之间的全基因座串扰的挑战可能为介导染色体易位到 IgH 基因座后癌基因失调控的机制提供有用的见解。
