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.