Genetic and epigenetic control of V gene rearrangement frequency.

The antibody repertoire is enormous and reflects the power of combinatorial and junctional diversity to generate avast repertoire with a moderate number of V, D and J gene segments. However, although there are many VH and VK gene segments, the usage of these genes is highly unequal. In this chapter, we summarize our studies elucidating many of the factors that contribute to this unequal rearrangement frequency of individual gene segments. Firstly, there is much natural variation in the sequence of the Recombination Signal Sequences (RSS) that flank each recombining gene. This genetic variation contributes greatly to unequal recombination frequencies. However, other factors also play a major role in recombination frequencies, as evidenced by the fact that some genes with identical RSS rearrange at very different frequencies in vivo. Analysis of these gene segments by chromatin immunoprecipitation (ChIP) suggests that differences in the structure of the chromatin associated with each gene is also a major factor in differential accessibility for rearrangement. Finally, transcription factors can direct accessibility for recombination, possibly by recruiting chromatin-modifying enzymes to the vicinity of the gene segment. Together, these factors dictate the composition of the newly formed antibody repertoire.