Figure 7 ∣. Loop extrusion mediates physiological, deletional class-switch recombination.

a ∣ Schematic of the 200 kb C_H region of the immunoglobulin heavy chain (Igh) locus, including the V(D)J exon, the intronic Igh enhancer iEμ, the various C_H exons with inducible (I) exon and promoter upstream of each C_H segment, S regions, the 3′ Igh regulatory region (3′IghRR) super-enhancer and the 3′ Igh CTCF sites. AID-initiated breaks within Sμ and an activated target Sγ1 are illustrated, which can lead to deletional or inversional class-switch recombination (CSR) outcomes for Sμ to Sγ1 joining. Deletional CSR is the major physiological event, whereas inversional CSR occurs at a lower frequency. Part a is adapted with permission from REF. 13. b ∣ Loop extrusion mediates formation of a class-switch recombination-centre (CSR-centre) and promotes the synapsis of S region double-strand break ends for deletional joining. In resting B cells (part i), cohesin is loaded at 3′ IghRR or iEμ–Sμ and then extrudes the 3′IghRR and iEμ–Sμ into proximity to generate a dynamic CSR-centre. In activated B cells (part ii), a primed S–C_H unit (Sγ1–Cγ1 is shown as an example) is extruded to the CSR-centre for transcriptional activation and cohesin loading, which leads to further extrusion to align acceptor and donor S regions (part iii). Tension pulls S region double-strand break ends initiated by AID into opposing cohesin rings (parts iv and v), stalling extrusion and aligning them for deletional joining mediated by non-homologous end joining (NHEJ) (part vi). Part b is adapted with permission from REF. 30. See also Supplementary Video 2.