Replacement of Sϵ with Sμ reveals novel mechanistic insights into rearrangements of the IgH locus and cMyc chromosomal translocations (P1400)

Abstract Preceding antibody constant regions are switch (S) regions varying in length and repeat density that are targets of activation induced cytidine deaminase (AID). We asked how participating S regions influence each other to orchestrate rearrangements at the IgH locus by engineering mice in which the weakest switch, Sϵ, is replaced with prominent recombination hotspot Sμ (SμKI). Inserted Sμ out-competed both endogenous Sγ1 and Sϵ to produce copious polyclonal IgE upon challenge, providing a platform to study IgE biology and therapeutic interventions. Intra-switch recombination (ISR) within endogenous Sμ is also diminished in SμKI mice, although the insertion itself exhibits no ISR. Furthermore, reciprocal translocations between c-myc and endogenous Sμ are dramatically lower in SμKI mice, suggesting the knocked-in switch sequesters critical factors. We propose competition among S regions influences CSR, ISR, and chromosomal translocation.