title: B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity.
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.
authors.affiliation: Genomics and Immunity, NIAMS, NIH, Bethesda, MD 20892, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Qian
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Genomics and Immunity, NIAMS, NIH, Bethesda, MD 20892, USA. Electronic address: marei.dose@nih.gov.
authors.forename: Marei
authors.initials: M
authors.lastname: Dose
authors.affiliation: Genomics and Immunity, NIAMS, NIH, Bethesda, MD 20892, USA.
authors.forename: Nathanael
authors.initials: N
authors.lastname: Pruett
authors.affiliation: Genomics and Immunity, NIAMS, NIH, Bethesda, MD 20892, USA.
authors.forename: Kyong-Rim
authors.initials: KR
authors.lastname: Kieffer-Kwon
authors.affiliation: Genomics and Immunity, NIAMS, NIH, Bethesda, MD 20892, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Resch
authors.affiliation: Genomics and Immunity, NIAMS, NIH, Bethesda, MD 20892, USA.
authors.forename: Genqing
authors.initials: G
authors.lastname: Liang
authors.affiliation: Department of Genetic and Development Biology, Jackson Laboratory for Genomic Medicine, University of Connecticut, 400 Farmington, CT 06030, USA.
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Genomics and Immunity, NIAMS, NIH, Bethesda, MD 20892, USA.
authors.forename: Ewy
authors.initials: E
authors.lastname: Mathé
authors.affiliation: The Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Benner
authors.affiliation: Center of Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Dubois
authors.affiliation: Genomics and Immunity, NIAMS, NIH, Bethesda, MD 20892, USA.
authors.forename: Steevenson
authors.initials: S
authors.lastname: Nelson
authors.affiliation: Genomics and Immunity, NIAMS, NIH, Bethesda, MD 20892, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Vian
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Thiago Y
authors.initials: TY
authors.lastname: Oliveira
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Mila
authors.initials: M
authors.lastname: Jankovic
authors.affiliation: Bar-Ilan University, Ramat-Gan 5290002, Israel.
authors.forename: Ofir
authors.initials: O
authors.lastname: Hakim
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Gazumyan
authors.affiliation: Institute of Molecular Pathology (IMP), Vienna BioCenter, Doktor Bohr Gasse 7, Vienna 1030, Austria.
authors.forename: Rushad
authors.initials: R
authors.lastname: Pavri
authors.affiliation: Science Applications International Corporation/Frederick, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
authors.forename: Parirokh
authors.initials: P
authors.lastname: Awasthi
authors.affiliation: Beijing Genomics Institute, Shenzhen, Shenzhen 518083, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Song
authors.affiliation: Beijing Genomics Institute, Shenzhen, Shenzhen 518083, China.
authors.forename: Geng
authors.initials: G
authors.lastname: Liu
authors.affiliation: Beijing Genomics Institute, Shenzhen, Shenzhen 518083, China.
authors.forename: Longyun
authors.initials: L
authors.lastname: Chen
authors.affiliation: Beijing Genomics Institute, Shenzhen, Shenzhen 518083, China.
authors.forename: Shida
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Science Applications International Corporation/Frederick, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.affiliation: Metabolism Branch, NCI, NIH, Bethesda, MD 20892, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Staudt
authors.affiliation: Division of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Cornelis
authors.initials: C
authors.lastname: Murre
authors.affiliation: Department of Genetic and Development Biology, Jackson Laboratory for Genomic Medicine, University of Connecticut, 400 Farmington, CT 06030, USA.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Davide F
authors.initials: DF
authors.lastname: Robbiani
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, 14186 Stockholm, Sweden.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Pan-Hammarström
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; HHMI, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.affiliation: 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.
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D063646:Carcinogenesis; D003564:Cytidine Deaminase / Q000235:genetics*; D004249:DNA Damage; D004742:Enhancer Elements, Genetic; D006801:Humans; D008223:Lymphoma / Q000378:metabolism; D051379:Mice; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase