Enhancer-instructed chromatin folding and compartmentalization dictate Vκ repertoire rearrangement to combat bacterial infection [RNA-seq]

Antigen receptor loci are organized into variable (V), diversity (D), and joining (J) elements that rearrange to generate diverse antigen receptor repertoires. Here, we identified an enhancer (E34) in the immunoglobulin kappa locus (Igκ) that instructed rearrangement of Vκ genes located in a sub-topologically associating domain (subTAD), including a Vκ gene encoding for antibodies targeting bacterial phosphorylcholine. E34 promoted the deposition of active histone marks across the E34 subTAD to instruct its nuclear repositioning from a V(D)J recombination-repressive compartment to a permissive one. E34-induced nuclear repositioning of the E34 subTAD promoted Vκ-Jκ interactions assisted by enhancer-associated epigenetic marks and de novo CTCF binding. Finally, we found that E34-instructed Vκ-Jκ rearrangement was essential to combat Streptococcus pneumoniae but not methicillin-resistant Staphylococcus aureus or influenza infections. These data show how enhancer-instructed chromatin topology mechanically pulls specific Vκ and Jκ genes into close physical proximity to generate distinct antibody repertoires to combat bacterial infection. Examination of histone modification, RNA, chromatin accesibility, CTCF binding, and chromatin conformation in pre-B cell from wild-type and enhancer-deleted mice in the V gene region of the Igk locus.