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- Title
An Igh distal enhancer modulates antigen receptor diversity by determining locus conformation.
- Authors
Bhat, Khalid H.; Priyadarshi, Saurabh; Naiyer, Sarah; Qu, Xinyan; Farooq, Hammad; Kleiman, Eden; Xu, Jeffery; Lei, Xue; Cantillo, Jose F.; Wuerffel, Robert; Baumgarth, Nicole; Liang, Jie; Feeney, Ann J.; Kenter, Amy L.
- 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. 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.
- Subjects
GENE rearrangement; LOCUS (Genetics); ARCHITECTURAL details; B cells; GENE clusters
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-36414-2