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 recombinase activating gene products (RAG) 1 and 2.  Diversity gene segments (DH) rearrange first, followed by variable (VH) gene rearrangements.  Here we provide evidence that each rearrangement step is guided by different rules of engagement between rearranging gene segments.  DH gene segments, that 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 WT IgH alleles, VH and DH gene segments can recombine with each other by both deletion and inversion of intervening DNA.  We propose that VH gene segments find their targets by diffusion-controlled mechanisms.  These distinct mechanisms may underlie differential allelic choice associated with each step of IgH gene assembly.