Fundamental roles of chromatin loop extrusion in antibody class switching

Xuefei Zhang, Yu Zhang, Zhaoqing Ba, Nia Kyritsis, Rafael Casellas and Frederick W. Alt ()
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Xuefei Zhang: Boston Children’s Hospital
Yu Zhang: Boston Children’s Hospital
Zhaoqing Ba: Boston Children’s Hospital
Nia Kyritsis: Boston Children’s Hospital
Rafael Casellas: Lymphocyte Nuclear Biology, NIAMS, NIH
Frederick W. Alt: Boston Children’s Hospital

Nature, 2019, vol. 575, issue 7782, 385-389

Abstract: Abstract Antibody class switch recombination (CSR) in B lymphocytes replaces immunoglobulin heavy chain locus (Igh) Cμ constant region exons (CHs) with one of six CHs lying 100–200 kb downstream1. Each CH is flanked upstream by an I promoter and long repetitive switch (S) region1. Cytokines and activators induce activation-induced cytidine deaminase (AID)2 and I-promoter transcription, with 3′ IgH regulatory region (3′ IgHRR) enhancers controlling the latter via I-promoter competition for long-range 3′ IgHRR interactions3–8. Transcription through donor Sμ and an activated downstream acceptor S-region targets AID-generated deamination lesions at, potentially, any of hundreds of individual S-region deamination motifs9–11. General DNA repair pathways convert these lesions to double-stranded breaks (DSBs) and join an Sμ-upstream DSB-end to an acceptor S-region-downstream DSB-end for deletional CSR12. AID-initiated DSBs at targets spread across activated S regions routinely participate in such deletional CSR joining11. Here we report that chromatin loop extrusion underlies the mechanism11 by which IgH organization in cis promotes deletional CSR. In naive B cells, loop extrusion dynamically juxtaposes 3′ IgHRR enhancers with the 200-kb upstream Sμ to generate a CSR centre (CSRC). In CSR-activated primary B cells, I-promoter transcription activates cohesin loading, leading to generation of dynamic subdomains that directionally align a downstream S region with Sμ for deletional CSR. During constitutive Sα CSR in CH12F3 B lymphoma cells, inversional CSR can be activated by insertion of a CTCF-binding element (CBE)-based impediment in the extrusion path. CBE insertion also inactivates upstream S-region CSR and converts adjacent downstream sequences into an ectopic S region by inhibiting and promoting their dynamic alignment with Sμ in the CSRC, respectively. Our findings suggest that, in a CSRC, dynamically impeded cohesin-mediated loop extrusion juxtaposes proper ends of AID-initiated donor and acceptor S-region DSBs for deletional CSR. Such a mechanism might also contribute to pathogenic DSB joining genome-wide.

Date: 2019
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DOI: 10.1038/s41586-019-1723-0

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