Altered 3D chromatin structure permits inversional recombination at the IgH locus

Immunoglobulin heavy chain ( ) genes are assembled by two sequential DNA rearrangement events that are initiated by recombination activating gene products (RAG) 1 and 2. Diversity (D ) gene segments rearrange first, followed by variable (V ) gene rearrangements. Here, we provide evidence that each rearrangement step is guided by different rules of engagement between rearranging gene segments. D gene segments, which recombine by deletion of intervening DNA, must be located within a RAG1/2 scanning domain for efficient recombination. In the absence of intergenic control region 1, a regulatory sequence that delineates the RAG scanning domain on wild-type alleles, V and D gene segments can recombine with each other by both deletion and inversion of intervening DNA. We propose that V gene segments find their targets by distinct mechanisms from those that apply to D gene segments. These distinctions may underlie differential allelic choice associated with each step of gene assembly.