CTCF-binding elements mediate control of V(D)J recombination
Immunoglobulin heavy chain (IgH) variable region exons are assembled from VH, D and JH gene segments in developing B lymphocytes. Within the 2.7-megabase mouse Igh locus, V(D)J recombination is regulated to ensure specific and diverse antibody repertoires. Here we report in mice a key Igh V(D)J recombination regulatory region, termed intergenic control region 1 (IGCR1), which lies between the VH and D clusters. Functionally, IGCR1 uses CTCF looping/insulator factor-binding elements and, correspondingly, mediates Igh loops containing distant enhancers. IGCR1 promotes normal B-cell development and balances antibody repertoires by inhibiting transcription and rearrangement of DH-proximal VH gene segments and promoting rearrangement of distal VH segments. IGCR1 maintains ordered and lineage-specific VH(D)JH recombination by suppressing VH joining to D segments not joined to JH segments, and VH to DJH joins in thymocytes, respectively. IGCR1 is also required for feedback regulation and allelic exclusion of proximal VH-to-DJH recombination. Our studies elucidate a long-sought Igh V(D)J recombination control region and indicate a new role for the generally expressed CTCF protein. The variable region of the immunoglobulin heavy chain (IgH) is generated by selecting one segment each from the VH, D and JH loci. Many studies have proposed the existence of a control region between the VH and D loci that would regulate VH-to-D recombination, but its identity has been elusive. Frederick Alt and colleagues have now located this regulatory sequence, IGCR1 (intergenic control region 1), and show that it uses CTCF sites to promote looping and interaction with distal enhancer elements. It also suppresses other events that would disrupt the ordered rearrangement of the VH, D and JH loci.