Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation
| العنوان: | Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation |
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| المؤلفون: | David G. Schatz, Jean-Marie Buerstedde, Suhas S.P. Rao, Jukka Alinikula, Filip Šenigl, Yaakov Maman, Ravi K. Dinesh, Lubomira Pecnova, David Weisz, Jiri Hejnar, Rafael Casellas, Rashu B. Seth, Arina D. Omer, Erez Lieberman Aiden |
| المصدر: | Cell reports Cell Reports, Vol 29, Iss 12, Pp 3902-3915.e8 (2019) |
| بيانات النشر: | Elsevier BV, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Somatic hypermutation, RNA polymerase II, Computational biology, Genome, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), Cell Line, Tumor, Cytidine Deaminase, Activation-induced (cytidine) deaminase, Humans, Enhancer, lcsh:QH301-705.5, Gene, Transcription factor, 030304 developmental biology, 0303 health sciences, biology, Lentivirus, Chromatin, 030104 developmental biology, Enhancer Elements, Genetic, HEK293 Cells, lcsh:Biology (General), Mutation, biology.protein, RNA Polymerase II, Somatic Hypermutation, Immunoglobulin, 030217 neurology & neurosurgery, Plasmids |
| الوصف: | SUMMARY 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. Graphical Abstract In Brief Senigl et al. show that genome susceptibility to somatic hypermutation (SHM) is confined within topologically associated domains (TADs) and is linked to markers of strong enhancers and stalled transcription and high levels of the cohesin loader NIPBL. Insertion of an ectopic SHM targeting element renders an entire TAD susceptible to SHM. |
| تدمد: | 1556-5068 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9a368ddd3906f056ea5c400d34747c64Test https://doi.org/10.2139/ssrn.3383796Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9a368ddd3906f056ea5c400d34747c64 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15565068 |
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