Biochemical and Biophysical Research Communications
Dioxin-responsive AHRE-II gene battery: identification by phylogenetic footprinting☆
Section snippets
Materials and methods
Extraction of genomic sequence. Complete genomic sequences were downloaded from the University of California, Santa Cruz (UCSC Golden Path) genome browser at http://genome.ucsc.edu. The releases used were: hg16 (human: NCBI build 34), mm4 (mouse: NCBI build 32), and rn3 (rat: Baylor v3.1). For each build we also downloaded the refLink and refFlat annotation tables which link LocusLink identifiers with gene symbols and with genomic locations, respectively. These tables were parsed with Perl
Motivation for phylogenetic footprinting
It is feasible to search all genes for all known transcription-factor binding-sites (TFBSs). Unfortunately the vast majority of binding-sites identified in this type of comprehensive search are biologically inactive false-positives. For example, TATA-box sequences are predicted to occur once every 250 bp throughout the entire genome. Some workers in the field have postulated a “Futility Theorem” saying that, to a first-approximation, all predicted TFBSs are non-functional [37]. Various methods
Discussion
Novel dioxin-responsive genes have been identified previously, both in microarray studies [42], [43], [44], [45] and by the careful study of individual genes and their promoters [46]. We combined these two approaches by using both genome-wide transcription-factor binding-site searches and genome-wide mRNA expression profiling. The use of phylogenetic footprinting across the three best-characterized mammalian genomes helped refine the candidate list of AHRE-II-regulated genes by 15-fold. Our
Acknowledgments
We thank the BioPerl, BioConductor, and DBI user support groups for implementation advice, Ms. Lan He for outstanding technical support with Affymetrix arrays, and Dr. Rafal Kustra for helpful discussions on statistical analyses. This study was funded by Grant MOP-57903 from the Canadian Institutes of Health Research to A.B.O., by Grant 200980 from the Academy of Finland to R.P. and Grant 53307 from the Academy of Finland Centre of Excellence Program to J.T.
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Abbreviations: We use the term AHRE to refer to the specific genomic regulatory nucleotide sequences that respond to the AH receptor and its agonist ligands. AHRE also is known as DRE (dioxin response element) or xenobiotic responsive element (XRE). AHR, aryl hydrocarbon receptor; ALDH3A2, aldehyde dehydrogenase 3A2; AnoC, anomalous Cyp1b1 complex; ARNT, aryl hydrocarbon receptor nuclear translocator; ER, estrogen receptor; LAC, ligand-activated coactivator; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TFBS, transcription-factor binding-site; TSS, transcription start site.