Chromosomal position of a V_H gene segment determines its activation and inactivation as a substrate for V(D)J recombination

Complete IgHC gene rearrangement occurs only in B cells in a stage-specific and ordered manner. We used gene targeting to reposition a distal V_H gene segment to a region just 5′ of the D_H gene cluster and found its activation to be highly dependent on the chromosomal domain within which it resides. The targeted V_H gene segment rearranged at a higher frequency than its endogenous counterpart, its rearrangement was no longer ordered, and its ability to be silenced by allelic exclusion was lost. Additionally, the targeted V_H gene segment lost lineage specificity, as VDJ_H rearrangement was observed in thymocytes. These data suggest that locus contraction, mimicked by proximal targeting, can override any regulation imposed by DNA sequences immediately surrounding V_H gene segments.