A B-Cell-Specific Enhancer Orchestrates Nuclear Architecture to Generate a Diverse Antigen Receptor Repertoire.

Summary 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. Graphical Abstract Highlights • An enhancer, E88, in the middle of the Igκ locus is a major hub of interactions • Deletion of E88 alters Vκ gene rearrangement frequencies throughout the locus • Structure of the Igκ locus in pro-B cells influences Vκ rearrangement in pre-B cells • V gene rearrangement is likely mediated in a subTAD-specific manner Barajas-Mora et al. demonstrate that an enhancer—E88—in the V gene region of the Igκ locus regulates long-range chromatin interactions, shaping its 3D structure, enabling different V-gene-containing subTADs to come in proximity to the J genes to generate a diverse repertoire. Consequently, E88 deletion perturbs the resulting B cell repertoire. [ABSTRACT FROM AUTHOR]