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Despite well-documented effects on human health, the action modes of environmental pollutants are incompletely understood. Although transcriptome-based approaches are widely used to predict associations between chemicals and disorders, the molecular cues regulating pollutant-derived gene expression changes remain unclear. Therefore, we developed a data-mining approach, termed DAR-ChIPEA, to identify transcription factors (TFs) playing pivotal roles in the action modes of pollutants.Large-scale public ChIP-Seq data (human, n=15,155; mouse, n=13,156) were used to predict TFs that are enriched in the pollutant-induced differentially accessible genomic regions (DARs) obtained from epigenome analyses (ATAC-Seq). The resultant pollutant-TF matrices were then cross-referenced to a repository of TF-disorder associations to account for pollutant modes of action. We subsequently evaluated the performance of the proposed method using a chemical perturbation data set to compare the outputs of the DAR-ChIPEA and our previously developed differentially expressed gene (DEG)-ChIPEA methods using pollutant-induced DEGs as input. We then adopted the proposed method to predict disease-associated mechanisms triggered by pollutants.The proposed approach outperformed other methods using the area under the receiver operating characteristic curve score. The mean score of the proposed DAR-ChIPEA was significantly higher than that of our previously described DEG-ChIPEA (0.7287 vs. 0.7060; Q=5.27810; two-tailed Wilcoxon rank-sum test). The proposed approach further predicted TF-driven modes of action upon pollutant exposure, indicating that (1) TFs regulating Th1/2 cell homeostasis are integral in the pathophysiology of tributyltin-induced allergic disorders; (2) fine particulates (PM) inhibit the binding of C/EBPs, Rela, and Spi1 to the genome, thereby perturbing normal blood cell differentiation and leading to immune dysfunction; and (3) lead induces fatty liver by disrupting the normal regulation of lipid metabolism by altering hepatic circadian rhythms.Highlighting genome-wide chromatin change upon pollutant exposure to elucidate the epigenetic landscape of pollutant responses outperformed our previously described method that focuses on gene-adjacent domains only. Our approach has the potential to reveal pivotal TFs that mediate deleterious effects of pollutants, thereby facilitating the development of strategies to mitigate damage from environmental pollution. 2023. BioMed Central Ltd., part of Springer Nature.

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Elucidating disease-associated mechanisms triggered by pollutants ... - Physician's Weekly