Regulation of somatic hypermutation by higher-order chromatin structure
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.
Authors
- Daniel Malzl (ORCID: https://orcid.org/0000-0001-5765-6375)
- Adriana Cantoran Garcia
- Rushad Pavri (ORCID: https://orcid.org/0000-0002-6191-6333)
- Ursula E. Schoeberl (ORCID: https://orcid.org/0000-0002-6105-5385)
- Marta Rizzi (ORCID: https://orcid.org/0000-0002-5153-6089)
- Mihaela Peycheva (ORCID: https://orcid.org/0000-0001-9268-0637)
- Maximilian von der Linde
- Johanna Fitz
- Israel Tojal da Silva (ORCID: https://orcid.org/0000-0002-4687-1499)
- Anton Goloborodko (ORCID: https://orcid.org/0000-0002-2210-8616)
- Renan Valieris (ORCID: https://orcid.org/0000-0002-8402-3175)
- Kimon Froussios (ORCID: https://orcid.org/0000-0003-2812-0525)
- Bernd Bauer
- Julia Costea
- Eva-Maria Wiedemann
- Jeremy Pflaum (ORCID: https://orcid.org/0009-0000-4878-8229)
- Franziska Schmidt
- Jeffrey H. Albrecht
- Bianca Bartl
Institutions
- Institute of Molecular Biotechnology (AT)
- University of Freiburg (DE)
- Research Institute of Molecular Pathology (AT)
- University Medical Center Freiburg (DE)
- Max Perutz Labs (AT)
- AC Camargo Hospital (BR)
- Vienna Biocenter (AT)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Molecular Cell
- Published
- 2025-06-27
- DOI
- https://doi.org/10.1016/j.molcel.2025.06.003
- Citations
- 1
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- Deutsche Forschungsgemeinschaft
- Austrian Science Fund