Dynamic zebrafish interactome reveals transcriptional mechanisms of dioxin toxicity.
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BACKGROUND: In order to generate hypotheses regarding the mechanisms by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) causes toxicity, we analyzed global gene expression changes in developing zebrafish embryos exposed to this potent toxicant in the context of a dynamic gene network. For this purpose, we also computationally inferred a zebrafish (Danio rerio) interactome based on orthologs and interaction data from other eukaryotes. METHODOLOGY/PRINCIPAL FINDINGS: Using novel computational tools to analyze this interactome, we distinguished between dioxin-dependent and dioxin-independent interactions between proteins, and tracked the temporal propagation of dioxin-dependent transcriptional changes from a few genes that were altered initially, to large groups of biologically coherent genes at later times. The most notable processes altered at later developmental stages were calcium and iron metabolism, embryonic morphogenesis including neuronal and retinal development, a variety of mitochondria-related functions, and generalized stress response (not including induction of antioxidant genes). Within the interactome, many of these responses were connected to cytochrome P4501A (cyp1a) as well as other genes that were dioxin-regulated one day after exposure. This suggests that cyp1a may play a key role initiating the toxic dysregulation of those processes, rather than serving simply as a passive marker of dioxin exposure, as suggested by earlier research. CONCLUSIONS/SIGNIFICANCE: Thus, a powerful microarray experiment coupled with a flexible interactome and multi-pronged interactome tools (which are now made publicly available for microarray analysis and related work) suggest the hypothesis that dioxin, best known in fish as a potent cardioteratogen, has many other targets. Many of these types of toxicity have been observed in mammalian species and are potentially caused by alterations to cyp1a.
Published Version (Please cite this version)10.1371/journal.pone.0010465
Publication InfoAlexeyenko, Andrey; Wassenberg, Deena M; Lobenhofer, Edward K; Yen, Jerry; Linney, Elwood; Sonnhammer, Erik LL; & Meyer, Joel N (2010). Dynamic zebrafish interactome reveals transcriptional mechanisms of dioxin toxicity. PloS one, 5(5). pp. e10465. 10.1371/journal.pone.0010465. Retrieved from https://hdl.handle.net/10161/4537.
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Professor Emeritus of Molecular Genetics and Microbiology
The research program in this laboratory has moved through different areas of interest, most of them involved with how embryonic cells develop. Our early work with embryonal carcinoma cells (EC cells, the conceptual precursor to embryonic stem cells) involved using viruses to determine the transcriptional control differences between stem and differentiated cell. We found the restriction to expression and replication of polyoma virus in EC cells could be overcome by isolated enhancer mutant
Truman and Nellie Semans/Alex Brown and Sons Associate Professor of Molecular Environmental Toxicology
Dr. Meyer studies the effects of toxic agents and stressors on human and wildlife health. He is particularly interested in understanding the mechanisms by which environmental agents cause DNA damage, the molecular processes that organisms employ to protect prevent and repair DNA damage, and genetic differences that may lead to increased or decreased sensitivity to DNA damage. Mitochondrial DNA damage and repair, as well as mitochondrial function in general, are a particular focus. He studies
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