| First Author | Zhang X | Year | 2019 |
| Journal | Nature | Volume | 575 |
| Issue | 7782 | Pages | 385-389 |
| PubMed ID | 31666703 | Mgi Jnum | J:287518 |
| Mgi Id | MGI:6407707 | Doi | 10.1038/s41586-019-1723-0 |
| Citation | Zhang X, et al. (2019) Fundamental roles of chromatin loop extrusion in antibody class switching. Nature 575(7782):385-389 |
| abstractText | Antibody class switch recombination (CSR) in B lymphocytes replaces immunoglobulin heavy chain locus (Igh) Cmu constant region exons (CHs) with one of six CHs lying 100-200 kb downstream(1). Each CH is flanked upstream by an I promoter and long repetitive switch (S) region(1). 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 interactions(3-8). Transcription through donor Smu and an activated downstream acceptor S-region targets AID-generated deamination lesions at, potentially, any of hundreds of individual S-region deamination motifs(9-11). General DNA repair pathways convert these lesions to double-stranded breaks (DSBs) and join an Smu-upstream DSB-end to an acceptor S-region-downstream DSB-end for deletional CSR(12). AID-initiated DSBs at targets spread across activated S regions routinely participate in such deletional CSR joining(11). Here we report that chromatin loop extrusion underlies the mechanism(11) 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 Smu 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 Smu for deletional CSR. During constitutive Salpha 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 Smu 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. |
