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Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation

F. Senigl, Y. Maman, RK. Dinesh, J. Alinikula, RB. Seth, L. Pecnova, AD. Omer, SSP. Rao, D. Weisz, JM. Buerstedde, EL. Aiden, R. Casellas, J. Hejnar, DG. Schatz,

. 2019 ; 29 (12) : 3902-3915.e8. [pub] 20191217

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20025398

Grantová podpora
R01 AI127642 NIAID NIH HHS - United States
T32 AI007019 NIAID NIH HHS - United States

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.

Citace poskytuje Crossref.org

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