Ovesen JL, Schnekenburger M, Puga A
Posttranslational histone modifications are a critical regulatory mechanism of gene transcription. Previous studies from our laboratory have shown that contingent on binding to its cognate promoter motifs in the Cyp1a1 gene, activation of the aryl hydrocarbon receptor (AHR) by benzo[a]pyrene (BaP) treatment induces histone modifications in the Cyp1a1 promoter that are required for activation of gene transcription. Here, we have studied different AHR ligands, including polychlorinated biphenyls (PCBs) of different toxic equivalency factors (TEF), to determine whether changes in histone modifications are linked to different levels of Cyp1a1 expression or dependent on AHR-ligand affinity. We find that all ligands lead to the same pattern of histone modifications in a relationship that parallels the strength of their AHR-ligand affinity. Thus, whereas PCB126 (TEF 0.1), 3-methylcholanthrene, β-naphthoflavone, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) initiate a pattern of histone marks similar to those induced by BaP, PCB77 (TEF 0.0001) causes a lower level of change in the same marks and requires a longer activation time than PCB126, BaP, or TCDD. In contrast, the non-dioxin-like PCB153 recruits AHR to the Cyp1a1 enhancer causing a displacement of enhancer-associated histone H3 but does not cause the other observed histone mark changes nor does it induce transcription. These results indicate that AHR recruitment to the promoter is not sufficient to induce the histone modifications needed to activate gene expression and show that there is a good correlation between the regulatory chromatin changes associated with ligand-induced AHR target gene transcription and the resultant toxicity of the ligand.