Regulation of immunoglobulin heavy-chain gene rearrangements

Regulated assembly of antigen receptor gene segments to produce functional genes is a hallmark of B- and T-lymphocyte development. The immunoglobulin heavy-chain (IgH) and T-cell receptor beta-chain genes rearrange first in B and T lineages, respectively. Both loci require two recombination events to assemble functional genes; D-to-J recombination occurs first followed by V-to-DJ recombination. Despite similarities in overall rearrangement patterns, each locus has unique regulatory features. Here, we review the characteristics of IgH gene rearrangements such as developmental timing, deletion versus inversion, DH gene segment utilization, ordered recombination of VH gene segments, and feedback inhibition of rearrangement in pre-B cells. We summarize chromatin structural features of the locus before and during recombination and, wherever possible, incorporate these into working hypotheses for understanding regulation of IgH gene recombination. The picture emerges that the IgH locus is activated in discrete, independently regulated domains. A domain encompassing DH and JH gene segments is activated first, within which recombination is initiated. VH genes are activated subsequently and, in part, by interleukin-7. These observations lead to a model for feedback inhibition of IgH rearrangements.