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

Immunoglobulin heavy chain (IgH) genes are assembled by two sequential DNA rearrangement events that are initiated by recombination activating gene products (RAG) 1 and 2. Diversity (D_H) gene segments rearrange first, followed by variable (V_H) gene rearrangements. Here, we provide evidence that each rearrangement step is guided by different rules of engagement between rearranging gene segments. D_H 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 IgH alleles, V_H and D_H gene segments can recombine with each other by both deletion and inversion of intervening DNA. We propose that V_H gene segments find their targets by distinct mechanisms from those that apply to D_H gene segments. These distinctions may underlie differential allelic choice associated with each step of IgH gene assembly.