Genome-wide screening of dioxin-responsive genes in fetal brain: bioinformatic and experimental approaches
Hideki Fujita1, Hazuki Samejima, Noriyuki Kitagawa
1Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
Abstract:
Many of the effects of dioxins, which are potent environmental pollutants and teratogens, are mediated through the aryl hydrocarbon receptor, also known as the dioxin receptor. The purpose of the present study was to characterize dioxin-responsive genes in a comprehensive manner using two complementary approaches: bioinformatic analysis and microarray analysis. First, we characterized the overall distribution of the cis-regulatory element for the dioxin-responsive element sequence (DRE) 'gcgtg' within putative promoter regions. We assembled the upstream sequences 10 kb from the transcription start site and evaluated their location and frequency in the human and mouse genomes. Second, we characterized the expression profile of mouse embryonic day 12 fetal brain exposed to 2,3,7,8-tetrarchlorodibenzo-p-dioxin. The distributions of 26,680 DREs among 2,843 human genes and 98,711 DREs among 18,541 mouse genes were examined. In both species, the DREs tended to be located close to the transcription start site. Forty genes exhibited significant induction or repression following dioxin exposure in fetal mice. The set of genes exhibited a strong functional coherence, with statistically significant enrichment in organogenesis and the DNA-dependent regulation of transcription, according to Gene Ontology annotations. In both humans and mice, DREs were preferentially distributed close to transcription start sites. Evolutionary conservation of this unique DRE distribution pattern suggests that DREs may be involved in transcriptional regulation. In mice, prenatal dioxin exposure altered the expression of 10 transcription factors, many of which have been documented to play a role in organogenesis. These genes may represent potential mediators of dioxin's effects in fetal tissues.
Insights
Dioxins affect development by altering gene expression through the aryl hydrocarbon receptor. This study identified dioxin-responsive genes and their regulatory elements, revealing key genes involved in organogenesis and transcriptional regulation.
Area of Science:
- Environmental toxicology
- Molecular biology
- Genomics
Background:
- Dioxins are potent environmental pollutants and teratogens.
- Their effects are primarily mediated by the aryl hydrocarbon receptor (AhR), also known as the dioxin receptor.
- Understanding dioxin-responsive genes is crucial for assessing developmental toxicity.
Purpose of the Study:
- To comprehensively characterize dioxin-responsive genes using bioinformatic and microarray analyses.
- To investigate the distribution and evolutionary conservation of dioxin-responsive elements (DREs).
- To identify genes and pathways affected by dioxin exposure during fetal development.
Main Methods:
- Bioinformatic analysis of DRE ('gcgtg') distribution in human and mouse promoter regions (10 kb upstream of transcription start site).
- Microarray analysis of gene expression in mouse embryonic day 12 fetal brain exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
- Gene Ontology analysis to determine functional enrichment of affected genes.
Main Results:
- DREs were preferentially located near transcription start sites in both human and mouse genomes.
- Prenatal dioxin exposure significantly altered the expression of 40 genes in fetal mice.
- Affected genes were enriched in functions related to organogenesis and DNA-dependent transcription regulation.
- Ten transcription factors involved in organogenesis showed altered expression.
Conclusions:
- The specific distribution pattern of DREs suggests their role in transcriptional regulation.
- Prenatal dioxin exposure impacts key genes involved in fetal development, particularly organogenesis.
- These identified genes may mediate the teratogenic effects of dioxins.
