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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Heindel, Jerrold
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Texas Agrilife Research
Schools of Earth Sciences/Natur
College Station
United States
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Ma, Xi; Chen, Jingshu; Tian, Yanan (2015) Pregnane X receptor as the ""sensor and effector"" in regulating epigenome. J Cell Physiol 230:752-7
Tian, Yanan (2013) Epigenetic regulation of pregnane X receptor activity. Drug Metab Rev 45:166-72
Ouyang, N; Ke, S; Eagleton, N et al. (2010) Pregnane X receptor suppresses proliferation and tumourigenicity of colon cancer cells. Br J Cancer 102:1753-61
Tian, Yanan (2009) Ah receptor and NF-kappaB interplay on the stage of epigenome. Biochem Pharmacol 77:670-80
Xie, Ying; Ke, Sui; Ouyang, Nengtai et al. (2009) Epigenetic regulation of transcriptional activity of pregnane X receptor by protein arginine methyltransferase 1. J Biol Chem 284:9199-205
Naspinski, Christine; Gu, Xinsheng; Zhou, Guo-Dong et al. (2008) Pregnane X receptor protects HepG2 cells from BaP-induced DNA damage. Toxicol Sci 104:67-73
Gu, Xinsheng; Ke, Sui; Liu, Duan et al. (2006) Role of NF-kappaB in regulation of PXR-mediated gene expression: a mechanism for the suppression of cytochrome P-450 3A4 by proinflammatory agents. J Biol Chem 281:17882-9
Chandra, Dhyan; Bratton, Shawn B; Person, Maria D et al. (2006) Intracellular nucleotides act as critical prosurvival factors by binding to cytochrome C and inhibiting apoptosome. Cell 125:1333-46
Tian, Yanan; Ke, Sui; Chen, Min et al. (2003) Interactions between the aryl hydrocarbon receptor and P-TEFb. Sequential recruitment of transcription factors and differential phosphorylation of C-terminal domain of RNA polymerase II at cyp1a1 promoter. J Biol Chem 278:44041-8
Tian, Yanan; Rabson, Arnold B; Gallo, Michael A (2002) Ah receptor and NF-kappaB interactions: mechanisms and physiological implications. Chem Biol Interact 141:97-115

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