An Igh distal enhancer modulates antigen receptor diversity by determining locus conformation

The mouse Igh locus is organized into a developmentally regulated topologically associated domain (TAD) that is divided into subTADs. Here we identify a series of distal V H enhancers (E VH s) that collaborate to configure the locus. E VH s engage in a network of long-range interactions that interconnect the subTADs and the recombination center at the D H J H gene cluster. Deletion of E VH 1 reduces V gene rearrangement in its vicinity and alters discrete chromatin loops and higher order locus conformation. Reduction in the rearrangement of the V H 11 gene used in anti-PtC responses is a likely cause of the observed reduced splenic B1 B cell compartment. E VH 1 appears to block long-range loop extrusion that in turn contributes to locus contraction and determines the proximity of distant V H genes to the recombination center. E VH 1 is a critical architectural and regulatory element that coordinates chromatin conformational states that favor V(D)J rearrangement.