Genome-Wide Computational Analysis of Dioxin Response Element Location and Distribution in the Human, Mouse, and Rat Genomes

Abstract

The aryl hydrocarbon receptor (AhR) mediates responses elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin by binding to dioxin response elements (DRE) containing the core consensus sequence 5′-GCGTG-3′. The human, mouse and rat genomes were computationally searched for all DRE cores. Each core was then extended by 7bp upstream and downstream, and matrix similarity (MS) scores for the resulting 19bp DRE sequences were calculated using a revised position weight matrix constructed from bona fide functional DREs. In total, 72,318 human, 70,720 mouse and 88,651 rat high-scoring (MS ≥ 0.8437) putative DREs were identified. Gene encoding intragenic DNA regions had ~1.6-times more putative DREs than the non-coding intergenic DNA regions. Furthermore, the promoter region spanning ±1.5kb of a TSS had the highest density of putative DREs within the genome. Chromosomal analysis found that the putative DRE densities of chromosomes X and Y were significantly lower than the mean chromosomal density. Interestingly, the 10kb upstream promoter region on chromosome X of the genomes were significantly less dense than the chromosomal mean, while the same region in chromosome Y was the most dense. In addition to providing a detailed genomic map of all DRE cores in the human, mouse and rat genomes, these data will further aid the elucidation of AhR-mediated signal transduction.

Xenobiotics and Loss of Cell Adhesion Drive Distinct Transcriptional Outcomes by Aryl Hydrocarbon Receptor Signaling

“…4). Similar genomic distribution has also been independently observed with the XRE core sequence (Dere et al, 2011). Of the 2665 XRE concatemer sites (defined as genome locations with four or more direct repeats of XRE cores), 78 of them fall within proximal promoter regions (Ϯ3 kb of TSS) of known genes (Supplemental Table 3).…”

“…We became interested in this XRE cluster site because no XRE core element was identified for Serpinb2 within 10 kb of its TSS, even though the XRE core is expected to occur every 512 bp on average (40 times in a 20-kb DNA fragment). The lack of XRE sites in close proximity to the Serpinb2 promoter is even more remarkable, given that previous genome-wide studies suggest that more than 99.98% of all mouse genes have at least one XRE core element within 10 kb of their TSS, regardless of whether they are AhR-responsive or not (Dere et al, 2011). We reasoned that although the identified XRE concatemer Fig.…”

Comparison of TCDD-elicited genome-wide hepatic gene expression in Sprague–Dawley rats and C57BL/6 mice

“…Putative DRE (pDRE) distributions within rat and mouse genes were identified using a position weight matrix (PWM) (Dere et al, 2011a). Briefly, mouse ChIP–chip analysis was performed using an Affymetrix GeneChip mouse 2.0R tiling array (Dere et al, 2011c).…”

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

“…Originally, Daniel Nebert described a battery of six AhR-dependent genes coding for xenobiotic metabolizing enzymes (Nebert, 1989). Today, the number of genes that respond to AhR activation by TCDD or other exogenous compounds is proposed to be on the order of 600 (Sartor et al, 2009;Dere et al, 2011). Among the most highly upregulated genes is the AhR repressor, which shares structural homology with AhR and ARNT (Mimura et al, 1999), and TiPARP (MacPherson et al, 2014).…”