IgH 3 ’ regulatory region increases ectopic class switch recombination

by Sandrine Le Noir, Am élie Bonaud, Bastien Hervé, Audrey Baylet, François Boyer, Sandrine Lecardeur, Zeliha Oruc, Christophe Sirac, Michel Cogné

DNA lesions inflicted by activation-induced deaminase (AID) instrumentally initiate the processes reshaping immunoglobulin genes in mature B-cells, from local somatic hypermutation (SHM) to junctions of distant breaks during class switch recombination (CSR). It remains incompletely understood how these divergent outcomes of AID attacks are differentially and temporally focused, with CSR strictly occurring in the Ig heavy chain (IgH) locus while SHM concentrates on rearranged V(D)J regions in theIgH and Ig light chain loci. In theIgH locus, disruption of either the 3 ’Regulatory Region (3’RR) super-enhancer or of switch (S) regions preceding constant genes, profoundly affects CSR. Reciprocally, we now examined if these elements are sufficient to induce CSR in a synthetic locus based on theIg κ locus backbone. Addition of a surrogate “core 3’RR” (c3’RR) and of a pair of transcribed and spliced Switch regions, together with a reporter system for “κ-CSR” yielded a switchableIg κ locus. While the c3 ’RR stimulated SHM at S regions, it also lowered the local SHM threshold necessary for switch recombination to occur. The 3’RR thus both helps recruit AID to initiate DNA lesions, but then also promotes their resolution through long-distance synapses and recombination following double-strand bre aks.

Source: PLoS Genetics - February 8, 2021 Category: Genetics & Stem Cells Authors: Sandrine Le Noir Source Type: research