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. Here the authors show enhancers in the Igh locus play a major role in configuring locus architecture and in V(D)J recombination, and identify a link between enhancer hub formation, locus contraction and cohesin-mediated loop extrusion.