An Igh novel enhancer modulates antigen receptor diversity by determining locus conformation
Bhat, K. H.; Priyadarshi, S.; Naiyer, S. L.; Qu, X.; Faroque, H.; Kleiman, E.; Xu, J.; Lei, X.; Cantillo, J. F.; Wuerffel, R.; Baumgarth, N.; Liang, J.; Kenter, A. L.; Feeney, A.
Show 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 VH 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 DHJH gene cluster. Deletion of NE1 alters discrete chromatin loops, higher order locus conformation, locus-wide VH 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 VH genes to the recombination center. NE1 is a critical architectural element that coordinates chromatin conformational states that favor VH gene transcription or V(D)J rearrangement.
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