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

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.

[1]  C. Jefcoate,et al.  Regulation of cytochrome P-450 (CYP) 1B1 in mouse Hepa-1 variant cell lines: A possible role for aryl hydrocarbon receptor nuclear translocator (ARNT) as a suppressor of CYP1B1 gene expression. , 1999, Molecular pharmacology.

[2]  H. Tilson,et al.  Neurochemical effects of polychlorinated biphenyls: an overview and identification of research needs. , 1997, Neurotoxicology.

[3]  I. Jonassen,et al.  Predicting gene regulatory elements in silico on a genomic scale. , 1998, Genome research.

[4]  G. Stancel,et al.  Synthetic estrogen 17α-ethinyl estradiol induces pattern of uterine gene expression similar to endogenous estrogen 17β-estradiol , 1999 .

[5]  Richard A Young,et al.  Deciphering gene expression regulatory networks. , 2002, Current opinion in genetics & development.

[6]  M. E. Hahn,et al.  Molecular evolution of two vertebrate aryl hydrocarbon (dioxin) receptors (AHR1 and AHR2) and the PAS family. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[7]  C. Jefcoate,et al.  Ah receptor regulation of mouse Cyp1B1 is additionally modulated by a second novel complex that forms at two AhR response elements. , 2003, Toxicology and applied pharmacology.

[8]  P. Brazhnik,et al.  Gene networks: how to put the function in genomics. , 2002, Trends in biotechnology.

[9]  M. Nakajima,et al.  Critical enhancer region to which AhR/ARNT and Sp1 bind in the human CYP1B1 gene. , 2003, Journal of biochemistry.

[10]  G. Stancel,et al.  Synthetic estrogen 17alpha-ethinyl estradiol induces pattern of uterine gene expression similar to endogenous estrogen 17beta-estradiol. , 1999, The Journal of pharmacology and experimental therapeutics.

[11]  Kenta Nakai,et al.  DBTSS: DataBase of human Transcriptional Start Sites and full-length cDNAs , 2002, Nucleic Acids Res..

[12]  T. Pineau,et al.  Identification of dioxin-responsive elements (DREs) in the 5' regions of putative dioxin-inducible genes. , 1996, Chemico-biological interactions.

[13]  T. Iyanagi,et al.  Xenobiotic Responsive Element-mediated Transcriptional Activation in the UDP-glucuronosyltransferase Family 1 Gene Complex (*) , 1996, The Journal of Biological Chemistry.

[14]  R. Tibshirani,et al.  Empirical bayes methods and false discovery rates for microarrays , 2002, Genetic epidemiology.

[15]  Xin Chen,et al.  TRANSFAC: an integrated system for gene expression regulation , 2000, Nucleic Acids Res..

[16]  T. Rushmore,et al.  Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. , 1990, The Journal of biological chemistry.

[17]  A Orimo,et al.  Efp as a primary estrogen‐responsive gene in human breast cancer , 2000, FEBS letters.

[18]  Y. Fujii‐Kuriyama,et al.  Cooperative Interaction between AhR·Arnt and Sp1 for the Drug-inducible Expression of CYP1A1 Gene (*) , 1996, The Journal of Biological Chemistry.

[19]  S. Safe,et al.  Identification of a motif within the 5' regulatory region of pS2 which is responsible for AP-1 binding and TCDD-mediated suppression. , 1997, Biochemistry.

[20]  R. Lindahl,et al.  The same xenobiotic response element is required for constitutive and inducible expression of the mammalian aldehyde dehydrogenase-3 gene. , 1999, Archives of biochemistry and biophysics.

[21]  J. Whitlock,et al.  Protein-DNA interactions at a dioxin-responsive enhancer. Analysis of six bona fide DNA-binding sites for the liganded Ah receptor. , 1993, The Journal of biological chemistry.

[22]  Y. Fujii‐Kuriyama,et al.  Location of regulatory elements responsible for drug induction in the rat cytochrome P-450c gene. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[23]  O. Hankinson,et al.  Orientation of the heterodimeric aryl hydrocarbon (dioxin) receptor complex on its asymmetric DNA recognition sequence. , 1995, Molecular pharmacology.

[24]  T. Werner,et al.  Target gene identification from expression array data by promoter analysis. , 2001, Biomolecular engineering.

[25]  P. Farnham,et al.  Identification of unknown target genes of human transcription factors using chromatin immunoprecipitation. , 2002, Methods.

[26]  G L Kimmel,et al.  Developmental and reproductive toxicity of dioxins and related compounds: cross-species comparisons. , 1993, Critical reviews in toxicology.

[27]  Y. Fujii‐Kuriyama,et al.  Regulatory DNA elements localized remotely upstream from the drug-metabolizing cytochrome P-450c gene. , 1986, Nucleic acids research.

[28]  T. Werner,et al.  MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data. , 1995, Nucleic acids research.

[29]  G. Church,et al.  Identifying regulatory networks by combinatorial analysis of promoter elements , 2001, Nature Genetics.

[30]  Y. Fujii‐Kuriyama,et al.  Inhibition of the Transcription of CYP1A1 Gene by the Upstream Stimulatory Factor 1 in Rabbits , 1997, The Journal of Biological Chemistry.

[31]  David Botstein,et al.  A systematic approach to reconstructing transcription networks in Saccharomyces cerevisiae , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Yan P. Yuan,et al.  Predicting function: from genes to genomes and back. , 1998, Journal of molecular biology.

[33]  K Frech,et al.  Software for the analysis of DNA sequence elements of transcription , 1997, Comput. Appl. Biosci..

[34]  S. Safe,et al.  Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). , 1990, Critical reviews in toxicology.

[35]  N. Kerkvliet,et al.  Aryl hydrocarbon receptor-deficient mice generate normal immune responses to model antigens and are resistant to TCDD-induced immune suppression. , 2001, Toxicology and applied pharmacology.

[36]  John H. White,et al.  Genome-wide identification of high-affinity estrogen response elements in human and mouse. , 2004, Molecular endocrinology.

[37]  Kenji Nakamura,et al.  Loss of teratogenic response to 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) in mice lacking the Ah (dioxin) receptor , 1997, Genes to cells : devoted to molecular & cellular mechanisms.

[38]  B. Pugh,et al.  Genome-wide analysis of protein-DNA interactions in living cells , 2001, Genome Biology.

[39]  G. Church,et al.  Conservation of DNA regulatory motifs and discovery of new motifs in microbial genomes. , 2000, Genome research.

[40]  D. Nebert,et al.  Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. , 2000, Biochemical pharmacology.

[41]  W Miller,et al.  Locus control regions of mammalian beta-globin gene clusters: combining phylogenetic analyses and experimental results to gain functional insights. , 1997, Gene.

[42]  Serafim Batzoglou,et al.  Eukaryotic regulatory element conservation analysis and identification using comparative genomics. , 2004, Genome research.

[43]  Andrew I Su,et al.  Genome-wide analysis of CREB target genes reveals a core promoter requirement for cAMP responsiveness. , 2003, Molecular cell.

[44]  John J. Wyrick,et al.  Genome-wide location and function of DNA binding proteins. , 2000, Science.

[45]  D. Church,et al.  Cross-species sequence comparisons: a review of methods and available resources. , 2003, Genome research.

[46]  D. Dorsa,et al.  Differential Transcriptional Regulation of Rat Vasopressin Gene Expression by Estrogen Receptor α and β1 , 2000 .

[47]  M. Goodman,et al.  Embryonic epsilon and gamma globin genes of a prosimian primate (Galago crassicaudatus). Nucleotide and amino acid sequences, developmental regulation and phylogenetic footprints. , 1988, Journal of molecular biology.

[48]  L. Poellinger,et al.  Dioxin receptor and C/EBP regulate the function of the glutathione S-transferase Ya gene xenobiotic response element , 1993, Molecular and cellular biology.

[49]  M. Chang,et al.  Xenobiotic-responsive element for the transcriptional activation of the rat Cu/Zn superoxide dismutase gene. , 1999, Biochemical and biophysical research communications.

[50]  D. Pasco,et al.  Suppression of CYP1A1 transcription by H2O2 is mediated by xenobiotic-response element. , 1998, Archives of biochemistry and biophysics.

[51]  C. Jefcoate,et al.  Characterization of the Mouse Cyp1B1 Gene , 1998, The Journal of Biological Chemistry.

[52]  H. Swanson,et al.  The AH-receptor: genetics, structure and function. , 1993, Pharmacogenetics.

[53]  G. Schieven,et al.  Molecular mechanisms of toxicant-induced immunosuppression: role of second messengers. , 1996, Annual review of pharmacology and toxicology.

[54]  S Rozen,et al.  Primer3 on the WWW for general users and for biologist programmers. , 2000, Methods in molecular biology.

[55]  D. Dorsa,et al.  Differential transcriptional regulation of rat vasopressin gene expression by estrogen receptor alpha and beta. , 2000, Endocrinology.

[56]  Y. Fujii‐Kuriyama,et al.  Characterization of xenobiotic responsive elements upstream from the drug-metabolizing cytochrome P-450c gene: a similarity to glucocorticoid regulatory elements. , 1987, Nucleic acids research.

[57]  H. Swanson,et al.  DNA Binding Specificities and Pairing Rules of the Ah Receptor, ARNT, and SIM Proteins (*) , 1995, The Journal of Biological Chemistry.

[58]  O. Hankinson.  The aryl hydrocarbon receptor complex. , 1995, Annual review of pharmacology and toxicology.

[59]  J. Whitlock,et al.  Protein-DNA interactions at a dioxin-responsive enhancer. Mutational analysis of the DNA-binding site for the liganded Ah receptor. , 1992, The Journal of biological chemistry.

[60]  R. Pollenz,et al.  Functional and physical interactions between the estrogen receptor Sp1 and nuclear aryl hydrocarbon receptor complexes. , 1998, Nucleic acids research.

[61]  S. Safe,et al.  Transcriptional activation of c-fos protooncogene by 17beta-estradiol: mechanism of aryl hydrocarbon receptor-mediated inhibition. , 1999, Molecular endocrinology.

[62]  P. Harper,et al.  Detection and characterization of a low affinity form of cytosolic Ah receptor in livers of mice nonresponsive to induction of cytochrome P1-450 by 3-methylcholanthrene. , 1989, Molecular pharmacology.

[63]  V. Vasiliou,et al.  Role of the Ah Receptor and the Dioxin‐Inducible [Ah] Gene Battery in Toxicity, Cancer, and Signal Transduction a , 1993, Annals of the New York Academy of Sciences.

[64]  C. B. Pickett,et al.  Transcriptional regulation of the rat NAD(P)H:quinone reductase gene. Identification of regulatory elements controlling basal level expression and inducible expression by planar aromatic compounds and phenolic antioxidants. , 1991, The Journal of biological chemistry.

[65]  Mouse Genome Sequencing Consortium.  Initial sequencing and comparative analysis of the mouse genome , 2002, Nature.

[66]  C Gennings,et al.  Identification of temporal patterns of gene expression in the uteri of immature, ovariectomized mice following exposure to ethynylestradiol. , 2003, Physiological genomics.

[67]  C Gennings,et al.  Temporal- and dose-dependent hepatic gene expression changes in immature ovariectomized mice following exposure to ethynyl estradiol. , 2004, Carcinogenesis.