A1 Refereed original research article in a scientific journal
Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation
Authors: Senigl F, Maman Y, Dinesh RK, Alinikula J, Seth RB, Pecnova L, Omer AD, Rao SSP, Weisz D, Buerstedde JM, Aiden EL, Casellas R, Hejnar J, Schatz DG
Publisher: CELL PRESS
Publication year: 2019
Journal: Cell Reports
Journal name in source: CELL REPORTS
Journal acronym: CELL REP
Volume: 29
Issue: 12
First page : 3902
Last page: 3915.e8
Number of pages: 22
ISSN: 2211-1247
DOI: https://doi.org/10.1016/j.celrep.2019.11.039
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/44068895
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.
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