Form follows function — the three-dimensional structure of antigen receptor gene loci

• The spatial conformation of antigen receptor gene loci directs V(D)J recombination.
• V(D)J recombination co-opted DNA looping as a mode of regulation.
• The sequence elements directing IGH locus structures arose gradually during evolution.

Antigen receptor genes are assembled during lymphocyte development from individual gene segments by a somatic gene rearrangement process named V(D)J recombination. This process is tightly regulated to ensure the generation of an unbiased broad primary repertoire of immunoglobulins and T cell receptors, and to prevent aberrant recombination products that could initiate lymphomagenesis. One important mode of regulation that has recently been discovered for the immunoglobulin heavy chain (IGH) gene locus is the adoption of distinct three-dimensional structures of the locus. Changes in the spatial conformation are thought to ensure the appropriate access of the V(D)J recombinase machinery at each developmental stage, and the formation of extensive chromosome loops has been implicated in allowing equal access to widely dispersed gene elements.