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

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 proB cells, these local domains engaged in long-range interactions across the Igh locus, which depend on the regulators Pax5, YY1, and CTCF. The large VH 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 E mu enhancer, IGCR1 insulator, or 30 regulatory region in the proximal Igh domain.