The Journal of Experimental Medicine
Rockland Immunochemicals for Research
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Published online 4 September 2001. doi:10.1084/jem.194.5.645
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© The Rockefeller University Press, 0022-1007/2001/9/645/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 5, September 3, 2001 645-656

Original Article

Localized Gene-specific Induction of Accessibility to V(D)J Recombination Induced by E2A and Early B Cell Factor in Nonlymphoid Cells

Peter Goebela, Noel Janneya, Joaquín R. Valenzuelaa, William J. Romanowb, Cornelis Murreb, and Ann J. Feeneya
a The Scripps Research Institute, Department of Immunology IMM-22, La Jolla, CA 92037
b Department of Biology, University of California at San Diego, La Jolla, CA 92093

Correspondence to: Ann J. Feeney, The Scripps Research Institute, Dept. of Immunology IMM-22, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Tel:858-784-2979 Fax:858-784-9190 E-mail:feeney{at}scripps.edu.

Accessibility of immunoglobulin (Ig) gene segments to V(D)J recombination is highly regulated and is normally only achieved in B cell precursors. We previously showed that ectopic expression of E2A or early B cell factor (EBF) with recombination activating gene (RAG) induces rearrangement of IgH and IgL genes in nonlymphoid cells. V{kappa}I genes throughout the locus were induced to rearrange after transfection with E2A, suggesting that the entire V{kappa} locus was accessible. However, here we show that Ig loci are not opened globally but that recombination is localized. Gene families are interspersed in the DH, V{kappa}, and V{lambda} loci, and we show that certain families and individual genes undergo high levels of recombination after ectopic expression of E2A or EBF, while other families within the same locus are not induced to rearrange. Furthermore, in some families, induction of germline transcription correlates with the level of induced recombination, while in others there is no correlation, suggesting that recombination is not simply initiated by induction of germline transcription. The induced repertoire seen at 24 hours does not change significantly over time indicating the absence of many secondary rearrangements and also suggesting a direct targeting mechanism. We propose that accessibility occurs in a local manner, and that binding sites for factors facilitating accessibility are therefore likely to be associated with individual gene segments.

Key Words: transcription factor, antibody diversity, recombination, antibody formation, Igs


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