Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI 48824, USA.
BMC Genomics. 2011 Jul 15;12:365. doi: 10.1186/1471-2164-12-365.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor (TF) that mediates responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Integration of TCDD-induced genome-wide AhR enrichment, differential gene expression and computational dioxin response element (DRE) analyses further elucidate the hepatic AhR regulatory network.
Global ChIP-chip and gene expression analyses were performed on hepatic tissue from immature ovariectomized mice orally gavaged with 30 μg/kg TCDD. ChIP-chip analysis identified 14,446 and 974 AhR enriched regions (1% false discovery rate) at 2 and 24 hrs, respectively. Enrichment density was greatest in the proximal promoter, and more specifically, within ± 1.5 kb of a transcriptional start site (TSS). AhR enrichment also occurred distal to a TSS (e.g. intergenic DNA and 3' UTR), extending the potential gene expression regulatory roles of the AhR. Although TF binding site analyses identified over-represented DRE sequences within enriched regions, approximately 50% of all AhR enriched regions lacked a DRE core (5'-GCGTG-3'). Microarray analysis identified 1,896 number of TCDD-responsive genes (|fold change| ≥ 1.5, P1(t) > 0.999). Integrating this gene expression data with our ChIP-chip and DRE analyses only identified 625 differentially expressed genes that involved an AhR interaction at a DRE. Functional annotation analysis of differentially regulated genes associated with AhR enrichment identified overrepresented processes related to fatty acid and lipid metabolism and transport, and xenobiotic metabolism, which are consistent with TCDD-elicited steatosis in the mouse liver.
Details of the AhR regulatory network have been expanded to include AhR-DNA interactions within intragenic and intergenic genomic regions. Moreover, the AhR can interact with DNA independent of a DRE core suggesting there are alternative mechanisms of AhR-mediated gene regulation.
芳香烃受体 (AhR) 是一种配体激活的转录因子 (TF)，可介导对 2,3,7,8-四氯二苯并对二恶英 (TCDD) 的反应。TCDD 诱导的全基因组 AhR 富集、差异基因表达和计算二恶英反应元件 (DRE) 分析的整合进一步阐明了肝 AhR 调控网络。
对经口给予 30μg/kg TCDD 的未成熟去卵巢小鼠肝组织进行了全局 ChIP-chip 和基因表达分析。ChIP-chip 分析分别在 2 小时和 24 小时确定了 14,446 和 974 个 AhR 富集区（假发现率为 1%）。富集密度在近端启动子最大，更具体地说，在转录起始位点 (TSS) 的 ± 1.5kb 范围内。AhR 也在 TSS 远端发生富集（例如基因间 DNA 和 3'UTR），扩展了 AhR 的潜在基因表达调控作用。虽然 TF 结合位点分析在富集区域内确定了过度表达的 DRE 序列，但大约 50%的 AhR 富集区域缺乏 DRE 核心 (5'-GCGTG-3')。微阵列分析确定了 1896 个 TCDD 反应基因（|fold change|≥1.5，P1(t)>0.999）。将此基因表达数据与我们的 ChIP-chip 和 DRE 分析整合，仅确定了 625 个差异表达基因，这些基因涉及 DRE 处的 AhR 相互作用。与 AhR 富集相关的差异调节基因的功能注释分析确定了与脂肪酸和脂质代谢和转运以及异生物质代谢相关的过度表达过程，这与 TCDD 引起的小鼠肝脂肪变性一致。
AhR 调控网络的细节已扩展到包括基因内和基因间基因组区域内的 AhR-DNA 相互作用。此外，AhR 可以与 DNA 相互作用而无需 DRE 核心，这表明存在 AhR 介导的基因调控的替代机制。
