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.

doi:10.1101/2022.05.23.492988

bioRxiv · 10.1101/2022.05.23.492988

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.

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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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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.. 2022-05-24. An Igh novel enhancer modulates antigen receptor diversity by determining locus conformation. https://doi.org/10.1101/2022.05.23.492988

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