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Replacement of Iγ3 germ-line promoter by Iγ1 inhibits class-switch recombination to IgG3

Oruc, Zeliha, Boumédiène, Ahmed, Le Bert, Marc, Khamlichi, Ahmed Amine
Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.51 pp. 20484-20489
immunoglobulin A, immunoglobulin E, immunoglobulin G, interleukin-4, loci, mice, models
Class-switch recombination (CSR) enables IgM-producing B cells to switch to the production of IgG, IgE, and IgA. The process requires germ-line (GL) transcription that initiates from promoters upstream of switch (S) sequences and is regulated by the 3' regulatory region (3'RR) located downstream of the Ig heavy chain (IgH) locus. How the 3'RR effect its long-range activation is presently unclear. We generated a mouse line in which Iγ3 GL promoter was replaced by Iγ1. We found that GL transcription could initiate from the inserted Iγ1 promoter and was induced by increased concentrations of IL-4 and that the transcripts were normally spliced. However, when compared with GL transcripts derived from the endogenous Iγ1 promoter in the same stimulation conditions, those from the inserted Iγ1 promoter were less abundant. CSR to Cγ3 was abrogated both in vivo and in vitro. The results strongly suggest that the endogenous Iγ1 promoter insulates the inserted Iγ1 from the long-range activating effect of the 3'RR. The implications of our findings are discussed in light of the prominent models of long-distance activation in complex loci.