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Convergent Sense/Antisense 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. While largely specific for immunglobulin 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 a mechanistic explanation for AID off-targeting to a small subset of mostly lineage-specific genes in activated B cells.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE62296 | GEO | 2014/12/04

SECONDARY ACCESSION(S): PRJNA263795

REPOSITORIES: GEO

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Convergent Sense/Antisense Transcription At Intragenic Super-Enhancers Targets AID-initiated Genomic Instability

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