Many levels of control of V gene rearrangement frequency.

V, D, and J gene segments rearrange at very different frequencies. As with most biological systems, there are multiple levels of control of V gene recombination frequency, and here we review some of the work from our laboratory that addresses these various control mechanisms. One of the important factors that affect non-random V gene rearrangement frequency is the natural heterogeneity in recombination signal sequences (RSSs). Not only does variation in the heptamer and nonamer affect rearrangement, but variation in the spacer can also dramatically affect recombination. However, there are clearly other factors which control V gene rearrangement, as revealed by the fact that genes with identical RSSs can rearrange at different frequencies in vivo. Some of these other influences most likely affect the earliest stages of control--the change from an inaccessible state to an accessible state. Transcription factors can play a role in inducing these changes. Rearrangement of many VkappaI genes can be induced in a non-lymphoid cell line after ectopic expression of E2A, while neighboring VkappaII and VkappaIII genes do not rearrange, demonstrating that at least one level of control of induction of accessibility occurs at the level of the individual gene. Also, changes in chromatin structure can affect accessibility and might influence individual V gene rearrangement frequency.