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.
Activation of the aryl hydrocarbon receptor (AhR(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 kappaB-Rel, HRE, PPAR gamma, GR, PAX-4 and estrogen receptor binding sites. Co-treatment experiments with TCDD and CoCl(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.
Frericks
Markus
M
Institute for Environmental Medical Research (IUF), 40225 Düsseldorf, Germany.
Burgoon
Lyle D
LD
Zacharewski
Timothy R
TR
Esser
Charlotte
C
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics*; D020239:Receptor Cross-Talk / Q000187:drug effects* / Q000502:physiology; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors