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

ABSTRACT The Igh locus is organized into a developmentally regulated topologically associated domain (TAD) that is divided into subTADs. Here we identify a series of novel enhancers (NEs) that collaborate to configure the locus, determine transcriptional potential in over a hundred functional V H genes and their usage in V(D)J recombination. NE1 engages 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 NE1 alters discrete chromatin loops, higher order locus conformation, locus-wide V H gene transcription and regional V gene utilization that is linked to a greatly reduced splenic B1 B cell compartment. NE1 blocks long-range loop extrusion that in turn contributes to locus contraction and determines the proximity of distant V H genes to the recombination center. NE1 is a critical architectural element that coordinates chromatin conformational states that favor V H gene transcription or V(D)J rearrangement.