Somatic hypermutation in variable heavy chain rearranged regions is abrogated in the absence of the 3′ regulatory region enhancer, whereas transcription rate in the Ig heavy chain is only partially reduced.

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.