title: Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability.
abstract: Activation-induced cytidine deaminase (AID) initiates both somatic hypermutation (SHM) for antibody affinity maturation and DNA breakage for antibody class switch recombination (CSR) via transcription-dependent cytidine deamination of single-stranded DNA targets. Though largely specific for immunoglobulin genes, AID also acts on a limited set of off-targets, generating oncogenic translocations and mutations that contribute to B cell lymphoma. How AID is recruited to off-targets has been a long-standing mystery. Based on deep GRO-seq studies of mouse and human B lineage cells activated for CSR or SHM, we report that most robust AID off-target translocations occur within highly focal regions of target genes in which sense and antisense transcription converge. Moreover, we found that such AID-targeting "convergent" transcription arises from antisense transcription that emanates from super-enhancers within sense transcribed gene bodies. Our findings provide an explanation for AID off-targeting to a small subset of mostly lineage-specific genes in activated B cells.
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Fei-Long
authors.initials: FL
authors.lastname: Meng
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Du
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Federation
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jiazhi
authors.initials: J
authors.lastname: Hu
authors.affiliation: Howard Hughes Medical Institute, 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, and Center of Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kyong-Rim
authors.initials: KR
authors.lastname: Kieffer-Kwon
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Meyers
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Corina
authors.initials: C
authors.lastname: Amor
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Caitlyn R
authors.initials: CR
authors.lastname: Wasserman
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Genomics and Immunity, NIAMS, and Center of Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
authors.affiliation: Howard Hughes Medical Institute, Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: james_bradner@dfci.harvard.edu.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: alt@enders.tch.harvard.edu.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D003564:Cytidine Deaminase / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D042822:Genomic Instability; D006801:Humans; D017578:Immunoglobulin Class Switching; D051379:Mice; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase