Critical roles of the immunoglobulin intronic enhancers in maintaining the sequential rearrangement of IgH and Igk loci

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Abstract
V(D)J recombination of immunoglobulin (Ig) heavy (IgH) and light chain genes occurs sequentially in the pro– and pre–B cells. To identify cis-elements that dictate this order of rearrangement, we replaced the endogenous matrix attachment region/Igk intronic enhancer (MiEκ) with its heavy chain counterpart (Eμ) in mice. This replacement, denoted EμR, substantially increases the accessibility of both Vκ and Jκ loci to V(D)J recombinase in pro–B cells and induces Igk rearrangement in these cells. However, EμR does not support Igk rearrangement in pre–B cells. Similar to that in MiEκ−/− pre–B cells, the accessibility of Vκ segments to V(D)J recombinase is considerably reduced in EμR pre–B cells when compared with wild-type pre–B cells. Therefore, Eμ and MiEκ play developmental stage-specific roles in maintaining the sequential rearrangement of IgH and Igk loci by promoting the accessibility of V, D, and J loci to the V(D)J recombinase.