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J. Biol. Chem., Vol. 279, Issue 6, 4110-4119, February 6, 2004

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Chromium Inhibits Transcription from Polycyclic Aromatic Hydrocarbon-inducible Promoters by Blocking the Release of Histone Deacetylase and Preventing the Binding of p300 to Chromatin^*

Yu-Dan Wei, Katherine Tepperman¶, Ming-ya Huang, Maureen A. Sartor, and Alvaro Puga||

From the Center for Environmental Genetics and Department of Environmental Health, University of Cincinnati College of Medicine and the ^¶Department of Biological Sciences, University of Cincinnati College of Arts and Sciences, Cincinnati, Ohio 45220-0056

Co-contamination with complex mixtures of carcinogenic metals, such as chromium, and polycyclic aromatic hydrocarbons is a common environmental problem with multiple biological consequences. Chromium exposure alters inducible gene expression, forms chromium-DNA adducts and chromium-DNA cross-links, and disrupts transcriptional activator-co-activator complexes. We have shown previously that exposure of mouse hepatoma Hepa-1 cells to chromate inhibits the induction of the Cyp1a1 and Nqo1 genes by dioxin. Here we have tested the hypothesis that chromium blocks gene expression by interfering with the assembly of productive transcriptional complexes at the promoter of inducible genes. To this end, we have studied the effects of chromium on the expression of genes induced by benzo[a]pyrene (B[a]P), another aryl hydrocarbon receptor agonist, and characterized the disruption of Cyp1a1 transcriptional induction by chromium. Gene expression profiling by using high density microarray analysis revealed that the inhibitory effect of chromium on B[a]P-dependent gene induction was generalized, affecting the induction of over 50 different genes involved in a variety of signaling transduction pathways. The inhibitory effect of chromium on Cyp1a1 transcription was found to depend on the presence of promoter-proximal sequences and not on the cis-acting enhancer sequences that bind the aryl hydrocarbon receptor-aryl hydrocarbon receptor nuclear translocator complex. By using transient reporter assays and chromatin immunoprecipitation analyses, we found that chromium prevented the B[a]P-dependent release of HDAC-1 from Cyp1a1 chromatin and blocked p300 recruitment. These results provide a mechanistic explanation for the observation that chromium inhibits inducible but not constitutive gene expression.

Received for publication, October 1, 2003 , and in revised form, November 11, 2003.

^* This work was supported by National Institutes of Health Grants R01 ES10708, P30 ES06096, and P42 ES04908 and by a grant from Phillip Morris. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: MPH Program, Fort Valley State University, Fort Valley, GA 31030.

^|| To whom correspondence should be addressed: Dept. of Environmental Health, University of Cincinnati Medical Center, P. O. Box 670056, Cincinnati, OH 45267-00567. Tel.: 513-558-0916; Fax: 513-558-0925; E-mail: Alvaro.Puga{at}UC.EDU.

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