Department of Molecular Biology, Umeå University, Umeå, Sweden.
Eur J Immunol. 2018 Oct;48(10):1687-1697. doi: 10.1002/eji.201847625. Epub 2018 Aug 28.
B lymphocytes optimize antibody responses by class switch recombination (CSR), which changes the expressed constant region exon of the immunoglobulin heavy chain (IgH), and by somatic hypermutation (SH) that introduces point mutations in the variable regions of the antibody genes. Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates both these antibody diversification processes by deaminating cytosine to uracil. Here we asked the question if transcription factors can mediate the specific targeting of the antibody diversification by recruiting AID. We have recently reported that AID is together with the transcription factors E2A, PAX5 and IRF4 in a complex on key sequences of the Igh locus. Here we report that also ETS1 is together with AID in this complex on key sequences of the Igh locus in splenic B cells of mice. Furthermore, we show that both ETS1 and PAX5 can directly recruit AID to DNA sequences from the Igh locus with the specific binding site for the transcription factor. Taken together, our findings support the notion of a targeting mechanism for the selective diversification of antibody genes with limited genome wide mutagenesis by recruitment of AID by PAX5 and ETS1 in a transcription factor complex.
B 淋巴细胞通过类别转换重组（CSR）优化抗体反应，该反应改变免疫球蛋白重链（IgH）表达的恒定区外显子，通过体细胞高频突变（SH）在抗体基因的可变区引入点突变。激活诱导的胞嘧啶脱氨酶（AID）是关键的诱变酶，通过将胞嘧啶脱氨为尿嘧啶，启动这两种抗体多样化过程。在这里，我们提出了一个问题，即转录因子是否可以通过招募 AID 来介导抗体多样化的特异性靶向。我们最近报道称，AID 与转录因子 E2A、PAX5 和 IRF4 一起存在于 Igh 基因座关键序列的复合物中。在这里，我们报告称，在小鼠脾脏 B 细胞中，ETS1 也与 AID 一起存在于 Igh 基因座关键序列的复合物中。此外，我们还表明，ETS1 和 PAX5 都可以直接将 AID 募集到来自 Igh 基因座的 DNA 序列上，该序列具有转录因子的特异性结合位点。综上所述，我们的研究结果支持了一种通过 PAX5 和 ETS1 在转录因子复合物中招募 AID 进行有限的全基因组诱变，从而对抗体基因进行选择性多样化的靶向机制的观点。
