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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • Cytidine Deaminase / metabolism*
  • Enhancer Elements, Genetic*
  • Genomic Instability*
  • Humans
  • Immunoglobulin Class Switching
  • Mice
  • Transcription Initiation Site
  • Transcription, Genetic*


  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase

Associated data

  • GEO/GSE62296