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Cell. 2014 Dec 18;159(7):1524-37. doi: 10.1016/j.cell.2014.11.013. Epub 2014 Dec 4.

B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity.

Author information

1
Genomics and Immunity, NIAMS, NIH, Bethesda, MD 20892, USA.
2
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
3
Genomics and Immunity, NIAMS, NIH, Bethesda, MD 20892, USA. Electronic address: marei.dose@nih.gov.
4
Department of Genetic and Development Biology, Jackson Laboratory for Genomic Medicine, University of Connecticut, 400 Farmington, CT 06030, USA.
5
The Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
6
Center of Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
7
Bar-Ilan University, Ramat-Gan 5290002, Israel.
8
Institute of Molecular Pathology (IMP), Vienna BioCenter, Doktor Bohr Gasse 7, Vienna 1030, Austria.
9
Science Applications International Corporation/Frederick, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
10
Beijing Genomics Institute, Shenzhen, Shenzhen 518083, China.
11
Metabolism Branch, NCI, NIH, Bethesda, MD 20892, USA.
12
Division of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA.
13
Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, 14186 Stockholm, Sweden.
14
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; HHMI, The Rockefeller University, New York, NY 10065, USA.
15
Genomics and Immunity, NIAMS, NIH, Bethesda, MD 20892, USA; Center of Cancer Research, NCI, NIH, Bethesda, MD 20892, USA. Electronic address: rafael.casellas@nih.gov.

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.

PMID:
25483777
PMCID:
PMC4272762
DOI:
10.1016/j.cell.2014.11.013
[Indexed for MEDLINE]
Free PMC Article

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