Chromatin conformation analysis reveals a multiway enhancer hub driving somatic hypermutation in human B cells, indicating that antibody diversification operates via non-competitive gene loops.
The generation of protective antibodies by somatic hypermutation (SHM) is essential for antibody maturation and adaptive immunity. SHM involves co-transcriptional mutagenesis of immunoglobulin variable (V) regions regulated by enhancers located hundreds of kilobases away. How 3D chromatin topology affects SHM is poorly understood. Here, we measure higher-order interactions on single alleles of the human immunoglobulin heavy-chain locus (IGH) using Tri-C. We find that SHM is underpinned by a multiway hub wherein the V region is proximal to all enhancers. Cohesin-mediated loop extrusion is dispensable for IGH transcription and hub architecture. Transcription and mutagenesis of IGH switch regions, which are necessary for antibody class-switch recombination, create new chromatin loops that can form without cohesin. However, these additional loops do not compromise hub integrity, V region transcription, or SHM. Thus, antibody maturation occurs within a multiway hub accommodating several gene-enhancer loops in which transcription and mutagenesis of different segments occur non-competitively.
No takes yet. Share an insight, caveat, or question.
Schoeberl et al. (2025) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: