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Title: Promoter analysis of TCDD-inducible genes in a thymic epithelial cell line indicates the potential for cell-specific transcription factor crosstalk in the AhR response

Abstract

Activation of the aryl hydrocarbon receptor (AhR{sup 1}) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits severe immunosuppression accompanied by thymic atrophy. Previous evidence suggests that TCDD targets both thymocytes and thymic epithelial cells. The AhR induces cell-specific changes in gene transcription via binding to the dioxin response element DRE; however, the underlying specificity-mechanisms, in particular with regard to the role of promoter element context, and possible transcription factor crosstalk remain poorly understood. Global gene expression in the cortical thymic epithelial cell line ET at 2, 4, and 6 h following 5 nM TCDD exposure resulted in differential regulation of 201 genes. JASPAR and TRANSFAC mapped the statistically over-represented promoter elements in the regulated genes to specific transcription factor binding sites, suggesting a regulatory role in AhR signaling. Over-represented elements included the xenobiotic response element XRE, NF{kappa}B-Rel, HRE, PPAR{gamma}, GR, PAX-4 and estrogen receptor binding sites. Co-treatment experiments with TCDD and CoCl{sub 2}, to induce hypoxia, or TCDD and 17-{beta}-estradiol (E2) indicated crosstalk between AhR and Hif or ER, in agreement with other experimental models. The computational identification of TFBS and the demonstration of interaction confirm their interactions with AhR signaling and suggest that the other over-represented elements may also be important in themore » immunosuppressive effects elicited by TCDD. In conclusion, we demonstrated the importance of promoter element cooperation in the shaping of a cell-specific AhR response. Our findings regarding the transcriptional changes in cortical epithelial cells are congruent with the well-known thymotoxic TCDD-phenotype, and useful in new hypothesis generation of the role of cortical TECs in TCDD toxicity.« less

Authors:
 [1]; ;  [2];  [1]
  1. Institute for Environmental Medical Research (IUF), 40225 Duesseldorf (Germany)
  2. Department of Biochemistry and Molecular Biology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State University (United States)
Publication Date:
OSTI Identifier:
21144144
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 232; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2008.07.009; PII: S0041-008X(08)00290-1; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANOXIA; ATROPHY; COBALT CHLORIDES; DIOXIN; EPITHELIUM; ESTRADIOL; GENES; GLUCOCORTICOIDS; HYDROCARBONS; IMMUNOSUPPRESSION; PHENOTYPE; POLYMERASE CHAIN REACTION; PROMOTERS; RECEPTORS; SPECIFICITY; THYMOCYTES; THYMUS; TOXICITY; TRANSCRIPTION; TRANSCRIPTION FACTORS

Citation Formats

Frericks, Markus, Burgoon, Lyle D, Zacharewski, Timothy R, and Esser, Charlotte. Promoter analysis of TCDD-inducible genes in a thymic epithelial cell line indicates the potential for cell-specific transcription factor crosstalk in the AhR response. United States: N. p., 2008. Web. doi:10.1016/j.taap.2008.07.009.
Frericks, Markus, Burgoon, Lyle D, Zacharewski, Timothy R, & Esser, Charlotte. Promoter analysis of TCDD-inducible genes in a thymic epithelial cell line indicates the potential for cell-specific transcription factor crosstalk in the AhR response. United States. https://doi.org/10.1016/j.taap.2008.07.009
Frericks, Markus, Burgoon, Lyle D, Zacharewski, Timothy R, and Esser, Charlotte. 2008. "Promoter analysis of TCDD-inducible genes in a thymic epithelial cell line indicates the potential for cell-specific transcription factor crosstalk in the AhR response". United States. https://doi.org/10.1016/j.taap.2008.07.009.
@article{osti_21144144,
title = {Promoter analysis of TCDD-inducible genes in a thymic epithelial cell line indicates the potential for cell-specific transcription factor crosstalk in the AhR response},
author = {Frericks, Markus and Burgoon, Lyle D and Zacharewski, Timothy R and Esser, Charlotte},
abstractNote = {Activation of the aryl hydrocarbon receptor (AhR{sup 1}) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits severe immunosuppression accompanied by thymic atrophy. Previous evidence suggests that TCDD targets both thymocytes and thymic epithelial cells. The AhR induces cell-specific changes in gene transcription via binding to the dioxin response element DRE; however, the underlying specificity-mechanisms, in particular with regard to the role of promoter element context, and possible transcription factor crosstalk remain poorly understood. Global gene expression in the cortical thymic epithelial cell line ET at 2, 4, and 6 h following 5 nM TCDD exposure resulted in differential regulation of 201 genes. JASPAR and TRANSFAC mapped the statistically over-represented promoter elements in the regulated genes to specific transcription factor binding sites, suggesting a regulatory role in AhR signaling. Over-represented elements included the xenobiotic response element XRE, NF{kappa}B-Rel, HRE, PPAR{gamma}, GR, PAX-4 and estrogen receptor binding sites. Co-treatment experiments with TCDD and CoCl{sub 2}, to induce hypoxia, or TCDD and 17-{beta}-estradiol (E2) indicated crosstalk between AhR and Hif or ER, in agreement with other experimental models. The computational identification of TFBS and the demonstration of interaction confirm their interactions with AhR signaling and suggest that the other over-represented elements may also be important in the immunosuppressive effects elicited by TCDD. In conclusion, we demonstrated the importance of promoter element cooperation in the shaping of a cell-specific AhR response. Our findings regarding the transcriptional changes in cortical epithelial cells are congruent with the well-known thymotoxic TCDD-phenotype, and useful in new hypothesis generation of the role of cortical TECs in TCDD toxicity.},
doi = {10.1016/j.taap.2008.07.009},
url = {https://www.osti.gov/biblio/21144144}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 232,
place = {United States},
year = {2008},
month = {10}
}