The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Toxicol Sci. 2010 Dec;118(2):454-69. doi: 10.1093/toxsci/kfq265. Epub 2010 Sep 6.
The aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters differentiation of B cells and suppresses antibody production. A combination of whole-genome, microarray-based chromatin immunoprecipitation (ChIP-on-chip), and time course gene expression microarray analysis was performed on the mouse B-cell line CH12.LX following exposure to lipopolysaccharide (LPS) or LPS and TCDD to identify the primary and downstream transcriptional elements of B-cell differentiation that are altered by the AHR. ChIP-on-chip analysis identified 1893 regions with a significant increase in AHR binding with TCDD treatment. Transcription factor binding site analysis on the ChIP-on-chip data showed enrichment in AHR response elements. Other transcription factors showed significant coenrichment with AHR response elements. When ChIP-on-chip regions were compared with gene expression changes at the early time points, 78 genes were identified as potential direct targets of the AHR. AHR binding and expression changes were confirmed for a subset of genes in primary mouse B cells. Network analysis examining connections between the 78 potential AHR target genes and three transcription factors known to regulate B-cell differentiation indicated multiple paths for potential regulation by the AHR. Enrichment analysis on the differentially expressed genes at each time point evaluated the downstream impact of AHR-regulated gene expression changes on B-cell-related processes. AHR-mediated impairment of B-cell differentiation occurred at multiple nodes of the B-cell differentiation network and potentially through multiple mechanisms including direct cis-acting effects on key regulators of B-cell differentiation, indirect regulation of B-cell differentiation-related pathways, and transcriptional coregulation of target genes by AHR and other transcription factors.
芳香烃受体 (AHR) 激动剂 2,3,7,8-四氯二苯并对二恶英 (TCDD) 改变 B 细胞的分化并抑制抗体产生。对 LPS 或 LPS 和 TCDD 暴露后的小鼠 B 细胞系 CH12.LX 进行了全基因组、基于微阵列的染色质免疫沉淀 (ChIP-on-chip) 和时间过程基因表达微阵列分析，以鉴定 AHR 改变的 B 细胞分化的主要和下游转录元件。ChIP-on-chip 分析鉴定出 1893 个与 TCDD 处理后 AHR 结合显著增加的区域。ChIP-on-chip 数据上的转录因子结合位点分析显示 AHR 反应元件富集。其他转录因子与 AHR 反应元件显示出显著的共富集。当将 ChIP-on-chip 区域与早期时间点的基因表达变化进行比较时，鉴定出 78 个基因作为 AHR 的潜在直接靶标。在原代小鼠 B 细胞中，对一小部分基因的 AHR 结合和表达变化进行了确认。检查已知调节 B 细胞分化的三个转录因子与 78 个潜在 AHR 靶基因之间连接的网络分析表明，AHR 具有多种潜在调节途径。在每个时间点评估差异表达基因的富集分析评估了 AHR 调节的基因表达变化对 B 细胞相关过程的下游影响。AHR 介导的 B 细胞分化损伤发生在 B 细胞分化网络的多个节点，并且可能通过多种机制，包括对 B 细胞分化关键调节剂的直接顺式作用、对 B 细胞分化相关途径的间接调节以及 AHR 和其他转录因子对靶基因的转录核心调节。
