TY - JOUR
T1 - Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability
AU - Meng, Fei Long
AU - Du, Zhou
AU - Federation, Alexander
AU - Hu, Jiazhi
AU - Wang, Qiao
AU - Kieffer-Kwon, Kyong Rim
AU - Meyers, Robin M.
AU - Amor, Corina
AU - Wasserman, Caitlyn R.
AU - Neuberg, Donna
AU - Casellas, Rafael
AU - Nussenzweig, Michel C.
AU - Bradner, James E.
AU - Liu, X. Shirley
AU - Alt, Frederick W.
N1 - Publisher Copyright:
© 2014 Elsevier Inc. All rights reserved.
PY - 2014/12/18
Y1 - 2014/12/18
N2 - 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.
AB - 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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U2 - 10.1016/j.cell.2014.11.014
DO - 10.1016/j.cell.2014.11.014
M3 - Article
C2 - 25483776
AN - SCOPUS:84919903836
SN - 0092-8674
VL - 159
SP - 1538
EP - 1548
JO - Cell
JF - Cell
IS - 7
ER -