Regulation of Bach2 by the aryl hydrocarbon receptor as a mechanism for suppression of B-cell differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Regulation of Bach2 by the aryl hydrocarbon receptor as a mechanism for suppression of B-cell differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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DOI：
10.1016/j.taap.2011.01.020
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发表时间：
2011-04-15
影响因子：
3.8
通讯作者：
Thomas RS
中科院分区：
文献类型：
--
作者：
De Abrew KN;Phadnis AS;Crawford RB;Kaminski NE;Thomas RS
接触芳烃受体 (AHR) 激动剂 2,3,7,8-四氯二苯并-对二恶英 (TCDD)，会改变 B 细胞分化并抑制抗体产生。先前对小鼠 B 细胞的基因组研究发现 Bach2 是 AHR 的直接靶标。已知 Bach2 通过与基因调控区域中的 Maf 元件 (MARE) 结合来抑制 Prdm1（参与 B 细胞分化的关键转录因子）的表达。在 TCDD 处理的脂多糖 (LPS) 激活的 B 细胞中进行染色质免疫沉淀，然后进行定量 PCR，结果显示 Bach2 基因第一个内含子内 AHR 的结合增加。通过电泳迁移率变动测定（EMSA）进一步证实了结合。 TCDD 还在处理后 2 至 24 小时内以时间和浓度依赖性方式诱导激活和静息 B 细胞中 Bach2 的表达。 Prdm1 的表达在 24 小时被 TCDD 降低，并且与 Bach2 的抑制一致。 EMSA 观察到随着 TCDD 浓度的增加，DNA 与内含子 5 MARE 的结合活性增加。 Supershifts 鉴定出 Bach2 在与 Prdm1 的内含子 5 MARE 相关的 DNA 结合复合物中的存在。使用 RNAi 对 Bach2 在 TCDD 抑制 B 细胞分化中的作用进行了功能验证。与对照相比，Bach2 的敲除显示 TCDD 诱导的 IgM 分泌抑制大约有 40% 的逆转。结果表明，AHR 对 Bach2 的转录调节是 TCDD 抑制 B 细胞分化的机制之一。
Exposure to the aryl hydrocarbon receptor (AHR) agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), alters B cell differentiation and suppresses antibody production. Previous genomic studies in mouse B cells identified Bach2 as a direct target of the AHR. Bach2 is known to repress expression of Prdm1, a key transcription factor involved in B cell differentiation, by binding to Maf elements (MAREs) in the regulatory regions of the gene. Chromatin immunopreciptiation followed by quantitative PCR in TCDD-treated lipopolysaccharide (LPS)-activated B cells showed increased binding of the AHR within the first intron in the Bach2 gene. The binding was further confirmed by electrophoretic mobility shift assay (EMSA). TCDD also induced expression of Bach2 in activated as well as resting B cells from 2 to 24 h post-treatment in a time and concentration-dependent manner. Expression of Prdm1 was decreased by TCDD at 24 h and was consistent with repression by Bach2. Increased DNA binding activity to the intron 5 MARE with increasing TCDD concentration was observed by EMSA. Supershifts identified the presence of Bach2 in the DNA binding complex associated with the intron5 MARE of Prdm1. Functional validation of the role of Bach2 in the suppression of B-cell differentiation by TCDD was performed using RNAi. Knockdown of Bach2 showed approximately 40% reversal in the TCDD-induced suppression of IgM secretion when compared to controls. The results suggest that the transcriptional regulation of Bach2 by the AHR is one of the mechanisms involved in the suppression of B-cell differentiation by TCDD.
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