CTCF-binding elements mediate control of V(D)J recombination

Immunoglobulin heavy chain (IgH) variable region exons are assembled from V-H, D and J(H) 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 V-H 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 D-H-proximal V-H gene segments and promoting rearrangement of distal V-H segments. IGCR1 maintains ordered and lineage-specific V-H(D)J(H) recombination by suppressing V-H joining to D segments not joined to J(H) segments, and V-H to DJ(H) joins in thymocytes, respectively. IGCR1 is also required for feedback regulation and allelic exclusion of proximal V-H-to-DJ(H) 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.