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

Nature communications 2023 Mar 03

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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 VH enhancers (EVHs) that collaborate to configure the locus. EVHs engage in a network of long-range interactions that interconnect the subTADs and the recombination center at the DHJH gene cluster. Deletion of EVH1 reduces V gene rearrangement in its vicinity and alters discrete chromatin loops and higher order locus conformation. Reduction in the rearrangement of the VH11 gene used in anti-PtC responses is a likely cause of the observed reduced splenic B1 B cell compartment. EVH1 appears to block long-range loop extrusion that in turn contributes to locus contraction and determines the proximity of distant VH genes to the recombination center. EVH1 is a critical architectural and regulatory element that coordinates chromatin conformational states that favor V(D)J rearrangement. © 2023. The Author(s).

Citation

Khalid H Bhat, Saurabh Priyadarshi, Sarah Naiyer, Xinyan Qu, Hammad Farooq, Eden Kleiman, Jeffery Xu, Xue Lei, Jose F Cantillo, Robert Wuerffel, Nicole Baumgarth, Jie Liang, Ann J Feeney, Amy L Kenter. An Igh distal enhancer modulates antigen receptor diversity by determining locus conformation. Nature communications. 2023 Mar 03;14(1):1225