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

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 and Amy L. Kenter ()
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Khalid H. Bhat: University of Illinois College of Medicine
Saurabh Priyadarshi: University of Illinois College of Medicine
Sarah Naiyer: University of Illinois College of Medicine
Xinyan Qu: University of Illinois College of Medicine
Hammad Farooq: University of Illinois Colleges of Engineering and Medicine
Eden Kleiman: Scripps Research
Jeffery Xu: Scripps Research
Xue Lei: University of Illinois Colleges of Engineering and Medicine
Jose F. Cantillo: University of Illinois College of Medicine
Robert Wuerffel: University of Illinois College of Medicine
Nicole Baumgarth: Johns Hopkins University
Jie Liang: University of Illinois Colleges of Engineering and Medicine
Ann J. Feeney: Scripps Research
Amy L. Kenter: University of Illinois College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-18

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 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.

Date: 2023
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DOI: 10.1038/s41467-023-36414-2

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