Identification of Positionally Conserved Dioxin Response Elements in Orthologous Human, Mouse and Rat Genes

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Author:	Lyle Burgoon
Organization:	Toxicogenomic Informatics and Solutions, LLC

SciCast Keywords

TCDD dioxin response element DRE positionally conserved Zacharewski Burgoon

Description

Computational identification and prediction of dioxin response elements (DREs) within gene regulatory regions is one method to identify novel, putative aryl hydrocarbon receptor (AhR) binding locations. This aids the phenotypic anchoring of toxicogenomic data to the AhR-signaling mechanism, as well as facilitates cross-species comparisons and more comprehensive microarray data interpretation. However, computationally identified putative DREs have a high false positive rate, which is further confounded by the frequent occurrence of the DRE core element (GCGTG) in the genome. The identification of positionally conserved DREs (the core plus flanking sequences) within orthologous human, mouse, and rat genes partially addresses this limitation by increasing the probability of identifying functional DREs. We use a position weight matrix (PWM) to identify putative DREs within regulatory regions (-10,000bp relative to the transcription start site through the 5’-UTR) of species-conserved and species-specific dioxin-responsive genes. Agglomerative hierarchical clustering of the DRE sequences across the human, mouse, and rat is then used to identify conserved DREs. In addition, an empirical distance threshold decreases the false positive clustering rate, and a map of the DREs across the three orthologous genes illustrates the positionally conserved orthologous DREs. Maps for conserved dioxin responsive genes, such as Cyp1a1, Cyp1b1, and Aldh3a1 identify the location of positionally conserved DREs in human, mouse and rat regulatory regions. This approach is being expanded to prioritize species-specific dioxin-responsive genes that warrant further validation. This method in combination with the identification of other regulatory elements may facilitate the elucidation of the regulatory grammar required for AhR-mediated gene regulation. Funded by NIEHS Superfund grant P42 ES04911.

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Poster Meeting: Society of Toxicology Meeting

Poster Date: March 17, 2008

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