B Cell Super-Enhancers and Regulatory Clusters Recruit AID Tumorigenic Activity.
Document Type
Article
Publication Date
12-18-2014
JAX Source
Cell 2014 Dec 18; 159(7):1524-37.
Volume
159
Issue
7
First Page
1524
Last Page
1537
ISSN
1097-4172
PMID
25483777
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. Cell 2014 Dec 18; 159(7):1524-37.
Recommended Citation
Qian J,
Wang Q,
Dose M,
Pruett N,
Kieffer-Kwon K,
Resch W,
Liang G,
Tang Z,
Mathé E,
Benner C,
Dubois W,
Nelson S,
Vian L,
Oliveira T,
Jankovic M,
Hakim O,
Gazumyan A,
Pavri R,
Awasthi P,
Song B,
Liu G,
Chen L,
Zhu S,
Feigenbaum L,
Staudt L,
Murre C,
Ruan Y,
Robbiani D,
Pan-Hammarström Q,
Nussenzweig M,
Casellas R.
B Cell Super-Enhancers and Regulatory Clusters Recruit AID Tumorigenic Activity. Cell 2014 Dec 18; 159(7):1524-37.