Chromium Cross-Links Histone Deacetylase 1-DNA Methyltransferase 1 Complexes to Chromatin, Inhibiting Histone-Remodeling Marks Critical for Transcriptional Activation▿

Transcriptional regulation of gene expression requires posttranslational modification of histone proteins, which, in concert with chromatin-remodeling factors, modulate chromatin structure. Exposure to environmental agents may interfere with specific histone modifications and derail normal patterns of gene expression. To test this hypothesis, we coexposed cells to binary mixtures of benzo[a]pyrene (B[a]P), an environmental procarcinogen that activates Cyp1a1 transcriptional responses mediated by the aryl hydrocarbon receptor (AHR), and chromium, a carcinogenic heavy metal that represses B[a]P-inducible AHR-mediated gene expression. We show that chromium cross-links histone deacetylase 1-DNA methyltransferase 1 (HDAC1DNMT1) complexes to Cyp1a1 promoter chromatin and inhibits histone marks induced by AHR-mediated gene transactivation, including phosphorylation of histone H3 Ser-10, trimethylation of H3 Lys-4, and various acetylation marks in histones H3 and H4. These changes inhibit RNA polymerase II recruitment without affecting the kinetics of AHR DNA binding. HDAC1 and DNMT1 inhibitors or depletion of HDAC1 or DNMT1 with siRNAs blocks chromium-induced transcriptional repression by decreasing the interaction of these proteins with the Cyp1a1 promoter and allowing histone acetylation to proceed. By inhibiting Cyp1a1 expression, chromium stimulates the formation of B[a]P DNA adducts. Epigenetic modification of gene expression patterns may be a key element of the developmental and carcinogenic outcomes of exposure to chromium and to other environmental agents. Contamination of human habitats with complex mixtures of polycyclic aromatic hydrocarbons and heavy metals is a common environmental health problem. Although exposure to background levels of toxic and carcinogenic compounds occurs naturally, exposures at significantly higher concentrations occur in occupational settings with agents coreleased from multiple sources. Primary among these are manufacturing processes and anthropogenic activities, such as fossil fuel combustion, municipal waste incineration, car exhaust, smelter activity, and others. Among the agents involved, chromium and benzo[a]pyrene (B[a]P) have ranked among the top 20 in the National Priority List of Hazardous Substances (http://www .atsdr.cdc.gov/cercla/05list.html) for as long as this list has been in existence. B[a]P is the model compound of carcinogenic polycyclic aromatic hydrocarbon biotransformation (10). B[a]P is activated primarily by the cytochrome P450 CYP1A1 and CYP1B1 enzymes, two heme-containing proteins responsible for the metabolic activation and detoxification of numerous xenobiotics. Bioactivation results in a wide range of oxygenated metabolites, some of which are highly carcinogenic (43). Cytochrome P450-catalyzed reactions lead to both the production and the detoxification of B[a]P reactive intermediates, among them 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-B[a]P (BPDE), the