Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Mol Cell. 2019 Jan 3;73(1):48-60.e5. doi: 10.1016/j.molcel.2018.10.013. Epub 2018 Nov 15.
The genome is organized into topologically associated domains (TADs) that enclose smaller subTADs. Here, we identify and characterize an enhancer that is located in the middle of the V gene region of the immunoglobulin kappa light chain (Igκ) locus that becomes active preceding the stage at which this locus undergoes V(D)J recombination. This enhancer is a hub of long-range chromatin interactions connecting subTADs in the V gene region with the recombination center at the J genes. Deletion of this element results in a highly altered long-range chromatin interaction pattern across the locus and, importantly, affects individual V gene utilization locus-wide. These results indicate the existence of an enhancer-dependent framework in the Igκ locus and further suggest that the composition of the diverse antibody repertoire is regulated in a subTAD-specific manner. This enhancer thus plays a structural role in orchestrating the proper folding of the Igκ locus in preparation for V(D)J recombination.
基因组组织成拓扑关联域（TADs），这些域包含更小的亚 TADs。在这里，我们鉴定并描述了一个增强子，它位于免疫球蛋白 κ 轻链（Igκ）基因座的 V 基因区域的中间，在该基因座经历 V(D)J 重组之前变得活跃。这个增强子是连接 V 基因区域的亚 TADs 与 J 基因处的重组中心的长距离染色质相互作用的中心。这个元件的缺失导致整个基因座上的长距离染色质相互作用模式发生了高度改变，重要的是，它影响了整个基因座上的各个 V 基因的利用。这些结果表明 Igκ 基因座中存在一个依赖增强子的框架，进一步表明多样化抗体库的组成以亚 TAD 特异性的方式受到调节。因此，这个增强子在为 V(D)J 重组做准备时，在协调 Igκ 基因座的正确折叠中发挥了结构作用。
