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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,
Language English Country United States
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
R01 AI127642
NIAID NIH HHS - United States
T32 AI007019
NIAID NIH HHS - United States
NLK
Cell Press Free Archives
from 2012
Directory of Open Access Journals
from 2012
Free Medical Journals
from 2012
Freely Accessible Science Journals
from 2012-01-26
Open Access Digital Library
from 2012-01-01
Open Access Digital Library
from 2012-01-26
- MeSH
- Cytidine Deaminase genetics metabolism MeSH
- HEK293 Cells MeSH
- Lentivirus MeSH
- Humans MeSH
- Mutation genetics MeSH
- Cell Line, Tumor MeSH
- Plasmids genetics MeSH
- RNA Polymerase II genetics metabolism MeSH
- Somatic Hypermutation, Immunoglobulin genetics MeSH
- Enhancer Elements, Genetic genetics MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
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 Theoretical Biological Physics Rice University Houston TX 77005 USA
Center of Cancer Research NCI NIH Bethesda MD 20892 USA
Große Venedig 20 31134 Hildesheim Germany
Institute of Biomedicine University of Turku Kiinamyllynkatu 10 20520 Turku Finland
Laboratory of Genome Integrity National Cancer Institute NIH Bethesda MD 20892 USA
References provided by Crossref.org
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