Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences

Abstract

Comparative approaches were used to identify human, mouse and rat dioxin response elements (DREs) in genomic sequences unambiguously assigned to a nucleotide RefSeq accession number. A total of 13 bona fide DREs, all including the substitution intolerant core sequence (GCGTG) and adjacent variable sequences, were used to establish a position weight matrix and a matrix similarity (MS) score threshold to rank identified DREs. DREs with MS scores above the threshold were disproportionately distributed in close proximity to the transcription start site in all three species. Gene expression assays in hepatic mouse tissue confirmed the responsiveness of 192 genes possessing a putative DRE. Previously identified functional DREs in well-characterized AhR-regulated genes including Cyp1a1 and Cyp1b1 were corroborated. Putative DREs were identified in 48 out of 2437 human-mouse-rat orthologous genes between -1500 and the transcriptional start site, of which 19 of these genes possessed positionally conserved DREs as determined by multiple sequence alignment. Seven of these nineteen genes exhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated regulation, although there were significant discrepancies between in vivo and in vitro results. Interestingly, of the mouse-rat orthologous genes with a DRE between -1500 and +1500, only 37% had an equivalent human ortholog. These results suggest that AhR-mediated gene expression may not be well conserved across species, which could have significant implications in human risk assessment.

Signaling pathway for 2,3,7,8-tetrachlorodibenzo- p-dioxin-induced TNF-α production in differentiated THP-1 human macrophages

“…In general, the ligand-activated AhR mediates the effect of TCDD by interacting with XRE in the 5'-flanking regions of target genes. However, AhR-regulated XREs have not been found in the 5'-flanking region of the human TNF-α gene (Sun et al, 2004). Therefore, it appears that other signaling pathway is involved rather than the ligand-activated AhR directly activates transcription of the TNF-α gene.…”

Langerhans Cell Maturation and Contact Hypersensitivity Are Impaired in Aryl Hydrocarbon Receptor-Null Mice

“…It is therefore not too surprising that epidermal cells secreted less GM-CSF in AhR-deficient cultures, in particular as the gene has four putative xenobiotic-responsive elements in its promoter (46). GM-CSF is relevant for LC maturation, that is, CD80 expression levels (47).…”

Discovery and verification of functional single nucleotide polymorphisms in regulatory genomic regions: Current and developing technologies

“…Computational methods for the identification of cis-regulatory sequences have been successfully applied to simple organisms such as yeast and worm, and while some methods have been plagued by high false positive rates in mammals primarily because of the very large quantity of intergenic sequence present [25], many recent new bioinformatics algorithms have improved prediction [26]. These include examining evolutionarily conserved regulatory sequences in upstream sequences of orthologous genes across species [7,[27][28][29] and identifying statistically over-represented motifs in the upstream regions of genes that are co-regulated in microarray expression profiles [26,30].…”