An Igh distal enhancer modulates antigen receptor diversity by determining locus conformation
Khalid Hussain Bhat, Saurabh Priyadarshi, Sarah Naiyer, Xiaoyu Qu, Hammad Farooq, Eden Kleiman, Jeffery Xu, Xue Lei, José Fernando Cantillo, Robert Wuerffel, Nicole Baumgarth, Jie Liang, Ann J. Feeney, Amy Kenter
Abstract
Abstract 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.