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; Amy L. Kenter

doi:10.1038/s41467-023-36414-2

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, Amy L. Kenter

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

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 V_H enhancers (E_VHs) that collaborate to configure the locus. E_VHs engage in a network of long-range interactions that interconnect the subTADs and the recombination center at the D_HJ_H gene cluster. Deletion of E_VH1 reduces V gene rearrangement in its vicinity and alters discrete chromatin loops and higher order locus conformation. Reduction in the rearrangement of the V_H11 gene used in anti-PtC responses is a likely cause of the observed reduced splenic B1 B cell compartment. E_VH1 appears to block long-range loop extrusion that in turn contributes to locus contraction and determines the proximity of distant V_H genes to the recombination center. E_VH1 is a critical architectural and regulatory element that coordinates chromatin conformational states that favor V(D)J rearrangement.

Original language	English (US)
Article number	1225
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-36414-2
State	Published - Dec 2023

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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title = "An Igh distal enhancer modulates antigen receptor diversity by determining locus conformation",

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.",

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doi = "10.1038/s41467-023-36414-2",

language = "English (US)",

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AU - Bhat, Khalid H.

AU - Priyadarshi, Saurabh

AU - Naiyer, Sarah

AU - Qu, Xinyan

AU - Farooq, Hammad

AU - Kleiman, Eden

AU - Xu, Jeffery

AU - Lei, Xue

AU - Cantillo, Jose F.

AU - Wuerffel, Robert

AU - Baumgarth, Nicole

AU - Liang, Jie

AU - Feeney, Ann J.

AU - Kenter, Amy L.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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

Abstract

ASJC Scopus subject areas

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