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Aryl Hydrocarbon Receptor Ligands of Widely Different Toxic Equivalency Factors Induce Similar Histone Marks in Target Gene Chromatin

Ovesen, Jerald Lee
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291408173

Abstract Details

2010, PhD, University of Cincinnati, Medicine: Cell and Molecular Biology.
Dioxin and dioxin like compounds (DLCs) are environmental contaminants released during many industrial processes. Halogenated and polycyclic aromatic hydrocarbons, such as 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), DLCs, and benzo[a]pyrene (BaP) are known or suspected human carcinogens and developmental teratogens and induce expression of the cytochrome P450 encoded by the substrate responsive CYP1A1 gene. CYP1A1 gene induction requires trans-activation by the heterodimeric transcriptional complex formed by ligand bound Aromatic Hydrocarbon Receptor (AHR) and the AHR Nuclear Translocator proteins (ARNT). We have shown that with BaP induced activation of Cyp1a1 gene expression in mouse hepatoma Hepa-1 cells, there is a concomitant change in the pattern of histone modifications associated with the Cyp1a1 promoter and distal enhancer. At the promoter of the Cyp1a1 gene this pattern of histone modification that accompanies BaP induced Cyp1a1 transcription includes trimethylation of Lys4 of histone H3 (3MeK4H3) and hyperacetylation of Lysine 14 of histone H3 (AcK14H3). At the distal enhancer of the Cyp1a1 gene BaP leads to an increase in phosphorylation of Ser10 on histone H3(pS10H3) and a hyperacetylation of Lysine 16 of histone H4 (AcK16H4). Here we find that in mouse embryonic fibroblast, treatment with BaP shows a similar increase in Cyp1a1 transcription as in Hepa-1 cells accompanied by at the same pattern of histone modifications at both the distal enhancer and proximal promoter as in Hepa-1 cells. In MEFs these changes are dependent on the AHR binding to BaP and MEFs with an AHR allele which encodes an AHR protein with low binding affinity for ligand do not elicit the same modifications of histone marks in the Cyp1a1 gene promoter or distal enhancer as those with an allele encoding an AHR protein with higher affinity for ligand. We determine that treatment with various different AHR ligands all lead to similar patterns of histone modifications upstream of the Cyp1a1 gene. Because coplanar PCBs are AHR ligands and have toxic effects similar to TCDD we used chromatin immunoprecipitation to determine if TCDD and the coplanar PCBs cause a similar fingerprint of epigenetic modification as BaP. Using PCBs of various toxicities relative to TCDD we found that all of the DLC-PCBs initiated expression of Cyp1a1 similar to TCDD at the same relative toxic equivalence. We found that for a PCB with a similar toxicity as TCDD, PCB126, there were similar changes in histone marks at the Cyp1a1 gene promoter and enhancer. Despite initiating similar Cyp1a1 expression levels PCB77, a PCB with a much lower toxicity than TCDD, caused lower recruitment of AHR to the enhancer of Cyp1a1 than a similarly toxic dose of TCDD. PCB77 also lead to different histone modifications at the promoter of the Cyp1a1 gene than a comparable treatment of TCDD. To determine the cause of these differences in PCB77 and TCDD induced responses we examined the timing of AHR activation in response to each treatment and found that PCB77 causes a lower level of AHR activation that last for a greater duration.
Alvaro Puga, PhD (Committee Chair)
Sohaib Khan, PhD (Committee Member)
Ying Xia, PhD (Committee Member)
Daniel Nebert, MD (Committee Member)
Susan Waltz, PhD (Committee Member)
108 p.
Cellular Biology
Aryl-Hydrocarbon Receptor; AHR; PCB; Dioxin

Recommended Citations

Citations

  • Ovesen, J. L. (2010). Aryl Hydrocarbon Receptor Ligands of Widely Different Toxic Equivalency Factors Induce Similar Histone Marks in Target Gene Chromatin [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291408173

    APA Style (7th edition)

  • Ovesen, Jerald. Aryl Hydrocarbon Receptor Ligands of Widely Different Toxic Equivalency Factors Induce Similar Histone Marks in Target Gene Chromatin. 2010. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291408173.

    MLA Style (8th edition)

  • Ovesen, Jerald. "Aryl Hydrocarbon Receptor Ligands of Widely Different Toxic Equivalency Factors Induce Similar Histone Marks in Target Gene Chromatin." Doctoral dissertation, University of Cincinnati, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291408173

    Chicago Manual of Style (17th edition)

ucin1291408173
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© 2010, some rights reserved.Creative Commons License Aryl Hydrocarbon Receptor Ligands of Widely Different Toxic Equivalency Factors Induce Similar Histone Marks in Target Gene Chromatin by Jerald Lee Ovesen is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.