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 (Mb) mouse IgH locus (IgH), V(D)J recombination is regulated to ensure specific and diverse antibody repertoires. Herein, we report a key IgH V(D)J recombination regulatory region, termed InterGenic Control Region-1 (IGCR1), that lies between the V(H) and D clusters. Functionally, IGCR1 employs 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)s and promoting rearrangement of distal V(H)s. IGCR1 maintains ordered and lineage-specific V(H)(D)J(H) recombination, respectively, by suppressing V(H) joining to Ds not joined to J(H)s and V(H) to DJ(H) joins in thymocytes. IGCR1 also is required to allow 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 implicate a new role for the generally expressed CTCF protein.