Somatic hypermutation (SHM) introduces point mutations into immunoglobulin (Ig) genes but also causes mutations in other parts of the genome. We have used lentiviral SHM reporter vectors to identify regions of the genome that are susceptible ("hot") and resistant ("cold") to SHM, revealing that SHM susceptibility and resistance are often properties of entire topologically associated domains (TADs). Comparison of hot and cold TADs reveals that while levels of transcription are equivalent, hot TADs are enriched for the cohesin loader NIPBL, super-enhancers, markers of paused/stalled RNA polymerase 2, and multiple important B cell transcription factors. We demonstrate that at least some hot TADs contain enhancers that possess SHM targeting activity and that insertion of a strong Ig SHM-targeting element into a cold TAD renders it hot. Our findings lead to a model for SHM susceptibility involving the cooperative action of cis-acting SHM targeting elements and the dynamic and architectural properties of TADs.

Center for Genome Architecture Baylor College of Medicine Houston TX 77030 USA

Center for Genome Architecture Baylor College of Medicine Houston TX 77030 USA; Center for Theoretical Biological Physics Rice University Houston TX 77005 USA

Department of Immunobiology Yale School of Medicine 300 Cedar Street Box 208011 New Haven CT 06520 8011 USA

Große Venedig 20 31134 Hildesheim Germany

Institute of Biomedicine University of Turku Kiinamyllynkatu 10 20520 Turku Finland

Institute of Molecular Genetics Academy of Sciences of the Czech Republic Videnska 1083 14220 Prague 4 Czech Republic

Laboratory of Genome Integrity National Cancer Institute NIH Bethesda MD 20892 USA

Lymphocyte Nuclear Biology NIAMS NIH Bethesda MD 20892 USA; Center of Cancer Research NCI NIH Bethesda MD 20892 USA

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