Abstract
Dioxins are one of the most potent anthropogenic poisons, causing systemic disorders in embryonic development and pathologies in adults. The mechanism of dioxin action requires an aryl hydrocarbon receptor (AhR), but the downstream mechanisms are not yet precisely clear. Here, we performed a meta-analysis of all available transcriptome datasets taken from human cell cultures exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Differentially expressed genes from different experiments overlapped partially, but there were a number of those genes that were systematically affected by TCDD. Some of them have been linked to toxic dioxin effects, but we also identified other attractive targets. Among the genes that were affected by TCDD, there are functionally related gene groups that suggest an interplay between retinoic acid, AhR, and Wnt signaling pathways. Next, we analyzed the upstream regions of differentially expressed genes and identified potential transcription factor (TF) binding sites overrepresented in the genes responding to TCDD. Intriguingly, the dioxin-responsive element (DRE), the binding site of AhR, was not overrepresented as much as other cis-elements were. Bioinformatics analysis of the AhR binding profile unveils potential cooperation of AhR with E2F2, CTCFL, and ZBT14 TFs in the dioxin response. We discuss the potential implication of these predictions for further dioxin studies.
Highlights
Environmental pollution by industrial emissions, waste incineration, and rocket fuel contributes to xenobiotics accumulation in the environment; these xenobiotics include a group of dioxin compounds, of which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic representative [1,2,3,4]
aryl hydrocarbon receptor (AhR) belongs to the helix-loop-helix basic domain PER-aryl hydrocarbon receptor nuclear translocator (ARNT)-SIM subfamily and regulates the expression of a large number of genes via dioxin-responsive elements (DREs), known as xenobiotic-responsive elements (XREs), and has the consensus 5 -TNGCGTG-3 [8]
To study the cellular response mechanisms to dioxin compounds, we performed a meta-analysis of all available RNA-seq and microarray human datasets obtained under the action of TCDD
Summary
Environmental pollution by industrial emissions, waste incineration, and rocket fuel contributes to xenobiotics accumulation in the environment; these xenobiotics include a group of dioxin compounds, of which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic representative [1,2,3,4]. The generally accepted concept of the dioxin action mechanism on the cells is that it serves as a ligand for ligand-activated transcription factor (TF) aryl hydrocarbon receptor (AhR). AhR belongs to the helix-loop-helix basic domain PER-ARNT-SIM (bHLH/PAS) subfamily and regulates the expression of a large number of genes via dioxin-responsive elements (DREs), known as xenobiotic-responsive elements (XREs), and has the consensus 5 -TNGCGTG-3 [8]. The AhR/Hsp complex translocates to the cell nucleus, where it decomposes, and AhR (with c p23) forms an active transcriptional complex with the aryl hydrocarbon receptor nuclear translocator (ARNT) [11]. The key transcription factor mediating the effects of dioxin is known, but the exact mechanisms at the cellular level are not yet clear and require further research
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