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

FeiLong Meng | Zendy; Zhou Du | Zendy; Alexander Federation | Zendy; Jiazhi Hu | Zendy; Qiao Wang | Zendy; Kyong-Rim Kieffer-Kwon | Zendy; Robin M. Meyers | Zendy; Corina Amor | Zendy; Caitlyn R. Wasserman | Zendy; Doneuberg | Zendy; Rafael Casellas | Zendy; Michel C. Nussenzweig | Zendy; James E. Bradner | Zendy; X. Shirley Liu | Zendy; Frederick W. Alt | Zendy

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

Author(s) -

FeiLong Meng,

Zhou Du,

Alexander Federation,

Jiazhi Hu,

Qiao Wang,

Kyong-Rim Kieffer-Kwon,

Robin M. Meyers,

Corina Amor,

Caitlyn R. Wasserman,

Doneuberg,

Rafael Casellas,

Michel C. Nussenzweig,

James E. Bradner,

X. Shirley Liu,

Frederick W. Alt

Publication year - 2014

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2014.11.014

Subject(s) - biology , cytidine deaminase , somatic hypermutation , enhancer , activation induced (cytidine) deaminase , immunoglobulin class switching , gene , genetics , transcription (linguistics) , transcription factor , immunoglobulin gene , genome instability , dna , b cell , antibody , dna damage , linguistics , philosophy

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.

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