Human antibody heavy chain variable region exon interacts with the 3' regulatory region to form a stable somatic hypermutation center.

Authors

Ying Guan, Mariia Mikhova, Zhuo Yang, Kai Xu, Shuxian Xie, Xin Lin, Adam Yongxin Ye, Taimor Williams, Jianshu Wang, David G Schatz, Frederick W Alt, Xi Chen

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 40. Pages e2625638123. Oct 06, 2026. Epub Sep 28, 2026.

Abstract

Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) of immunoglobulin heavy chain (HC) variable region exons in germinal center (GC) B cells, allowing selection of affinity-matured B cell receptors. The V(D)J exon location is "privileged" for SHM targeting of diverse sequences within it. In analogy to the related HC class switch recombination center, we proposed that cohesin-mediated loop extrusion juxtaposes widely separated enhancers, including 3' Igh regulatory region ("3'RR"), with the V(D)J exon in GC B cells to establish a SHM-center (SHM-C) "privileged" for AID access. To test this hypothesis, we employed a human RAMOS GC B lymphoma cell SHM model with inducible AID expression in which we targeted an unmutated mouse HC V(D)J exon in place of its human counterpart. Activation of AID expression in this cycling RAMOS line for 10 d led to robust SHM accumulation in the mouse V(D)J exon with a pattern similar to that in mouse GC B cells. In this model, the mouse V(D)J exon was indeed juxtaposed to the two human 3'RRs and other elements consistent with SHM-C formation. While deletion of individual 3'RRs had little effect, deletion of both greatly reduced SHM, but left V(D)J exon transcription unabated. Moreover, the SHM-C and SHM accumulation remained intact over a 10-d period in viably G1-arrested and viably G1-arrested RAD21 (cohesin)-depleted versions of the model. We discuss implications for SHM-C structure and function, its long-term functional stability in the absence of the loop extrusion process proposed to assemble it, and for 3'RR SHM functions beyond transcriptional activation.

PMID:
42804635
Bibliographic data and abstract were imported from PubMed on 29 Sep 2026.

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