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

The Igκ locus, which is spread over 3Mb 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<inf>κ</inf> 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 Igκ 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 Igκ gene rearrangements. Hereby, the intronic and 3' Igκ enhancer elements coordinately focus their activities in the V<inf>κ</inf> region toward frequently used V<inf>κ</inf> 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<inf>κ</inf>-J<inf>κ</inf> intervening region and control Igκ locus contraction and V<inf>κ</inf> repertoire diversity. This involves CTCF-mediated locus insulation, restricting enhancer activity to the V<inf>κ</inf> region and suppressing the preferential recombination to proximal V<inf>κ</inf> genes. A picture emerges in which the dynamic control of long-range genomic interactions ensures correct timing of Igκ locus recombination and provides appropriate opportunities for individual V<inf>κ</inf> gene segments to engage in V<inf>κ</inf>-J<inf>κ</inf> rearrangement.

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