Flexible Long-Range Loops in the VH Gene Region of the Igh Locus Facilitate the Generation of a Diverse Antibody Repertoire

Summary The immunoglobulin heavy-chain ( Igh ) locus undergoes large-scale contraction in pro-B cells, which facilitates V H -DJ H recombination by juxtaposing distal V H genes next to the DJ H -rearranged gene segment in the 3′ proximal Igh domain. By using high-resolution mapping of long-range interactions, we demonstrate that local interaction domains established the three-dimensional structure of the extended Igh locus in lymphoid progenitors. In pro-B cells, these local domains engaged in long-range interactions across the Igh locus, which depend on the regulators Pax5, YY1, and CTCF. The large V H gene cluster underwent flexible long-range interactions with the more rigidly structured proximal domain, which probably ensures similar participation of all V H genes in V H -DJ H recombination to generate a diverse antibody repertoire. These long-range interactions appear to be an intrinsic feature of the V H gene cluster, because they are still generated upon mutation of the Eμ enhancer, IGCR1 insulator, or 3′ regulatory region in the proximal Igh domain.