Localized Epigenetic Changes Induced by D(H) Recombination Restricts Recombinase to DJ(H) Junctions

Immunoglobulin heavy chain (Igh) genes are assembled by sequential rearrangements of diversity (D(H)) and variable (V(H)) gene segments. Three critical constraints govern V(H) recombination. These include timing (V(H) recombination follows D(H) recombination), precision (V(H)s recombine only to DJ(H) junctions) and allele specificity (V(H) recombination is restricted to DJ(H) recombined alleles). We provide a model for these universal features of V(H) recombination. Analyses of DJ(H) recombined alleles revealed that DJ(H) junctions were selectively epigenetically marked, became nuclease sensitive and bound RAG proteins, thereby permitting D(H)-associated recombination signal sequences to initiate the second step of Igh gene assembly. We propose that V(H) recombination is precise because these changes did not extend to germline D(H) gene segments located 5′ of the DJ(H) junction.