Abstract
The antibody gene mutator activation-induced cytidine deaminase (AID) promiscuously damages oncogenes, leading to chromosomal translocations and tumorigenesis. Why nonimmunoglobulin loci are susceptible to AID activity is unknown. Here, we study AID-mediated lesions in the context of nuclear architecture and the B cell regulome. We show that AID targets are not randomly distributed across the genome but are predominantly grouped within super-enhancers and regulatory clusters. Unexpectedly, in these domains, AID deaminates active promoters and eRNA+ enhancers interconnected in some instances over megabases of linear chromatin. Using genome editing, we demonstrate that 3D-linked targets cooperate to recruit AID-mediated breaks. Furthermore, a comparison of hypermutation in mouse B cells, AID-induced kataegis in human lymphomas, and translocations in MEFs reveals that AID damages different genes in different cell types. Yet, in all cases, the targets are predominantly associated with topological complex, highly transcribed super-enhancers, demonstrating that these compartments are key mediators of AID recruitment.
Original language | English |
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Pages (from-to) | 1524-1537 |
Number of pages | 14 |
Journal | Cell |
Volume | 159 |
Issue number | 7 |
DOIs | |
State | Published - 18 Dec 2014 |
Bibliographical note
Publisher Copyright:© 2014 Elsevier Inc. All rights reserved.
Funding
We thank Daniel Hodson for isolating GC B cells, Ethan Tyler for designing Figure S7 B, Gustavo Gutierrez for technical assistance with deep-sequencing, David Bosque and Tom Eisenreich for managing the mouse colonies, and Jim Simone, Klara Velinzon, and Yelena Shatalina for FACS sorting. This work was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Cancer Institute (NCI), the Jackson Laboratory fund (JAX19020120), the European Research Council (ERC) (242551-ImmunoSwitch), and NIH grant AI037526 to M.C.N. M.C.N. is a Howard Hughes Medical Institute (HHMI) Investigator. Animal experiments were performed according to NIH and Rockefeller approved protocols. This study used the high-performance computational capabilities of NIH Helix Systems ( http://helix.nih.gov ).
Funders | Funder number |
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Jackson Laboratory fund | JAX19020120 |
National Institutes of Health | |
Howard Hughes Medical Institute | |
National Cancer Institute | |
National Institute of Allergy and Infectious Diseases | R37AI037526 |
National Institute of Arthritis and Musculoskeletal and Skin Diseases | |
European Commission | 242551-ImmunoSwitch |