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

Jason Qian, Qiao Wang, Marei Dose, Nathanael Pruett, Kyong Rim Kieffer-Kwon, Wolfgang Resch, Genqing Liang, Zhonghui Tang, Ewy Mathé, Christopher Benner, Wendy Dubois, Steevenson Nelson, Laura Vian, Thiago Y. Oliveira, Mila Jankovic, Ofir Hakim, Anna Gazumyan, Rushad Pavri, Parirokh Awasthi, Bin SongGeng Liu, Longyun Chen, Shida Zhu, Lionel Feigenbaum, Louis Staudt, Cornelis Murre, Yijun Ruan, Davide F. Robbiani, Qiang Pan-Hammarström, Michel C. Nussenzweig, Rafael Casellas

Research output: Contribution to journalArticlepeer-review

202 Scopus citations


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 languageEnglish
Pages (from-to)1524-1537
Number of pages14
Issue number7
StatePublished - 18 Dec 2014

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© 2014 Elsevier Inc. All rights reserved.


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