Meng Fei-Long, Du Zhou, Federation Alexander, Hu Jiazhi, Wang Qiao, Kieffer-Kwon Kyong-Rim, Meyers Robin M, Amor Corina, Wasserman Caitlyn R, Neuberg Donna, Casellas Rafael, Nussenzweig Michel C, Bradner James E, Liu X Shirley, Alt Frederick W
Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
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.
激活诱导的胞苷脱氨酶（AID）通过对单链DNA靶标的转录依赖性胞苷脱氨作用，启动抗体亲和力成熟的体细胞高频突变（SHM）以及抗体类别转换重组（CSR）中的DNA断裂。尽管AID在很大程度上对免疫球蛋白基因具有特异性，但它也作用于有限的一组脱靶位点，产生致癌易位和突变，从而导致B细胞淋巴瘤。AID如何被招募到脱靶位点一直是个长期的谜团。基于对激活进行CSR或SHM的小鼠和人类B系细胞的深度GRO-seq研究，我们报告称，最强烈的AID脱靶易位发生在靶基因的高度聚焦区域内，在这些区域中，正义链和反义链转录会汇聚。此外，我们发现这种靶向AID的“汇聚”转录源自反义转录，该反义转录来自正义链转录基因体内的超级增强子。我们的研究结果为AID在活化B细胞中靶向一小部分大多为谱系特异性基因的脱靶现象提供了解释。
