Chromosomal position of a VH 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 VH 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 VH 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 VH gene segments.