Convergent Transcription at Intragenic Super-Enhancers Targets AID-Initiated Genomic Instability

• AID off-target activity is associated with sense/antisense convergent transcription
• AID off-targeting occurs within intragenic SEs in mouse and human B lineage cells
• Strongly convergently transcribed intragenic SEs are predominant AID off-targets
• Ectopically expressed AID in fibroblasts targets convergently transcribed SEs

SummaryActivation-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.

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