The ∼28-kb 39 regulatory region (39RR), which is located at the most distal 39 region of the Ig H chain locus, has multiple regulatory functions that control IgH expression, class-switch recombination (CSR), and somatic hypermutation. In this article, we report that deletion of the entire 39RR in a mouse B cell line that is capable of robust cytokine-dependent CSR to IgA results in reduced, but not abolished, CSR. These data suggest that 39RR is not absolutely required for CSR and, thus, is not essential for targeting activation-induced cytidine deaminase to S regions, as was suggested. Moreover, replacing 39RR with a DNA fragment including only its four DNase I hypersensitive sites (lacking the large spacer regions) restores CSR to a level equivalent to or even higher than in wild-Type cells, suggesting that the four hypersensitive sites contain most of the CSR-promoting functions of 39RR. Stimulated cells express abundant germline transcripts, with the presence or absence of 39RR, providing evidence that 39RR has a role in promoting CSR that is unique from enhancing S region transcription. The Journal of Immunology, 2016, 197: 2930-2935.
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