In mature B cells, class switch recombination (CSR) replaces the expressed constant Cm gene with a downstream C H gene. How the four transcriptional enhancers of the IgH 3 0 regulatory region (3 0 RR) control CSR remains an open question. We have investigated IgG 1 CSR in 3 0 RR-deficient mice. Here we show that the 3 0 RR enhancers target the S g1 acceptor region (and poorly the S m donor region) by acting on epigenetic marks, germline transcription, paused RNA Pol II recruitment, R loop formation, AID targeting and double-strand break generation. In contrast, location and diversity of S m -S g1 junctions are not affected by deletion of the 3 0 RR enhancers. Thus, the 3 0 RR controls the first steps of CSR by priming the S acceptor region but is not implicated in the choice of the end-joining pathway.

Unlike classical class-switch recombination, class switching to IgD occurs independently of the IgH 3′ regulatory region.