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Cell. 2014 Dec 18;159(7):1538-48. doi: 10.1016/j.cell.2014.11.014. Epub 2014 Dec 4.

Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability.

Author information

1
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.
2
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.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
4
Howard Hughes Medical Institute, Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
5
Genomics and Immunity, NIAMS, and Center of Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
6
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115, USA.
7
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.
8
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.

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.

PMID:
25483776
PMCID:
PMC4322776
DOI:
10.1016/j.cell.2014.11.014
[Indexed for MEDLINE]
Free PMC Article

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