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.