Dynamic Control of Long-Range Genomic Interactions at the Immunoglobulin κ Light-Chain Locus

The Ig kappa locus, which is spread over 3 Mb of genomic DNA and contains > 100 variable (V) genes, serves as an important model system to study long-range chromatin interactions. Here, we will discuss how in developing B cells in the bone marrow the accessibility of individual V-kappa segments is controlled by many lineage-specific and ubiquitously expressed transcription factors that act on various cis-regulatory elements, including promoters, enhancers, and insulators. This dynamic control furthermore involves changes in subnuclear localization, histone modification, DNA demethylation, and three-dimensional locus compaction. In pro-B cells, the Ig kappa locus adopts a poised conformation as full contraction has been achieved and many key transcription factors already occupy the locus. Subsequently, the combined activation of pre-B cell antigen receptor signaling pathways and attenuation of IL-7R signaling in small resting pre-B cells dramatically modifies the transcription factor landscape, supporting the induction of monoallelic Ig kappa gene rearrangements. Hereby, the intronic and 30 Ig kappa enhancer elements coordinately focus their activities in the V-kappa region toward frequently used V-kappa genes. Recent work has drawn attention to the intriguing role of the CTCF-associated regulatory elements Cer and Sis, which are located in the V-kappa-J(kappa) intervening region and control Ig kappa locus contraction and V-kappa repertoire diversity. This involves CTCF-mediated locus insulation, restricting enhancer activity to the V-kappa region and suppressing the preferential recombination to proximal V-kappa genes. A picture emerges in which the dynamic control of long-range genomic interactions ensures correct timing of Ig kappa locus recombination and provides appropriate opportunities for individual V-kappa gene segments to engage in V-kappa-J(kappa) rearrangement.