Abstract
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.
Highlights
Aromatic Hydrocarbon Receptor (AHR) protein with higher affinity for ligand
We find that the same histone modification can be found in mouse embryo fibroblasts (MEFs) cells, and we firmly establish that the modifications are dependent on AHR ligand induced activation
We find that PCB77 treatment initiated histone modifications that seemed to be transitional between the marks associated with active and inactive gene transcription
Summary
The Aryl hydrocarbon receptor (AHR) is a member of the basic helix-loophelix/Per-ARNT-SIM (bHLH/PAS) family transcription factors. AHR interacts with RB, blocking p300 recruitment to E2F dependent gene promoters, and this ligand dependent interaction increases RBs suppression of E2F function and the cell’s entrance into S phase (Puga et al.,2000;Marlowe et al.,2004;Ge and Elferink,1998) This AHR ligand mediated enhancement of the RB regulated G1 arrest is one mechanism through which TCDD inhibits proliferation and DNA synthesis. Treatment with TCDD in utero, and to a lesser extent after birth, in both rats and mice cause slower development of the prostate and lower prostate size in an AHR dependent manner (Mably, Moore, and Peterson,1992;Gray, Ostby, and Kelce,1997;Simanainen et al.,2004;Theobald and Peterson,1997;Lin et al.,2002) These effects were not due to induced AHR responsive gene products metabolizing androgen receptor targets, nor by TCDDs anti-estrogenic effects (Lin et al.,2004;Ko, Moore, and Peterson,2004;Vezina et al.,2008). We find that non-dioxin-like PCB153 leads to recruitment of AHR to the Cyp1a1 enhancer but the histone modifications associated with activation of transcription do not occur
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