Dioxin and related halogenated aromatic hydrocarbons are ubiquitous, persistent environmental contaminants causing adverse responses to human and wildlife. Most of the toxic responses induced by dioxin are mediated by the aryl hydrocarbon receptor (AhR). Therefore, central to our understanding of dioxin-induced toxicity is to elucidate the mechanism of the AhR-regulated gene expressions. In earlier studies, we have found a physical association and functional reciprocal repression between the AhR and NF-kB pathways (J. Biol. Chem. 274,510). Because NF-kB is a pleiotropic transcription factor involved in many physiological functions that are known to be adversely affected by dioxin, the AhR-mediated suppression of NF-kB offers a mechanism for some aspects of hitherto poorly understood dioxin-induced toxic responses, such as the immune suppression and abnormal skin proliferation. Reciprocally, suppression of AhR by NF-kB activation has also offered an underlying mechanism for the long-standing observation that inflammatory cytokines and lipopolysaccharide suppress AhR-regulated cytochrome P450 1A1/1A2 and decrease capacity of xenobiotic (including clinical drugs) metabolism (J. Biol. Chem. 276,39638). In recent studies, by using chromatin immunoprecipitation (CHIP) assay, we have obtained new results revealing that the AhR/NF-kB interaction converges at level of transcription involving (1) control of transcription elongation and (2) chromatin modifications.
In AIM I of this proposal we will investigate a mechanism in which AhR/NF-kB interaction regulates cyp1a1 transcription elongation by directly interacting with p-TEFb (positive transcription elongation factor b), which plays a critical role in elongation control.
In AIM II, we will investigate histone modifications (histone acetylation and methylation) in response to the diametrically opposing actions of AhR and NF-kB and to establish the residue-specific and combinatorial patterns of histone modifications (histone code) associated with """"""""on and off"""""""" states of cyp1a1. We will also investigate a novel AhR interactive protein (identified by CytoTrap yeast two hybrid screening) SUV39H2 methyltransferase for its role in AhR-mediated gene silencing, which may be important for male imprinting. The proposed studies will help us gain mechanistic understandings of the functions of AhR and NF-kB in normal physiology as well as pathogenesis induced by dioxin and related compounds.
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