Dataset Information

Conserved genomic structure of the Cyp1a1 and Cyp1a2 loci and their dioxin responsive elements cluster.

ABSTRACT: A thorough DNA sequence analysis reveals that the mouse Cyp1a1 and Cyp1a2 loci are located with coding directions opposite to each other. The two genes are separated by approximately 13.9 kb of genomic DNA containing no open reading frames (mCyp1a1_1a2 junction). Within the mCyp1a1_1a2 junction, eight consensus dioxin responsive elements (DREs) are present and seven of the eight DREs located less than 1.4 kb upstream from the Cyp1a1 transcriptional start site. The genomic structure of mouse Cyp1a1 and Cyp1a2 loci is similar to that of human CYP1A1 and CYP1A2 loci. In the human CYP1A1 and CYP1A2 are also arranged in a head to head orientation and separated by a 23 kb genome junction (hCyp1A1_1A2). Comparative sequence analysis between these two genomic junctions demonstrated that the 1.4kb upstream region from the transcriptional start site of mouse Cyp1a1 was highly conserved with that of human CYP1A1. In contrast, there are no conserved DREs in the proximal upstream region of Cyp1a2. The "head to head" genomic structure and position of the DREs cluster region near the Cyp1a1 gene on Cyp1a1_1a2 were confirmed in cattle, dog and rat genome. These results suggest that the conservation of genomic structure of Cyp1a1 and Cyp1a2 genes, and the DREs cluster are important in mammalian biology.

SUBMITTER: Nukaya M

PROVIDER: S-EPMC2658877 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Conserved genomic structure of the Cyp1a1 and Cyp1a2 loci and their dioxin responsive elements cluster.

Nukaya Manabu M Bradfield Christopher A CA

Biochemical pharmacology 20081106 4

A thorough DNA sequence analysis reveals that the mouse Cyp1a1 and Cyp1a2 loci are located with coding directions opposite to each other. The two genes are separated by approximately 13.9 kb of genomic DNA containing no open reading frames (mCyp1a1_1a2 junction). Within the mCyp1a1_1a2 junction, eight consensus dioxin responsive elements (DREs) are present and seven of the eight DREs located less than 1.4 kb upstream from the Cyp1a1 transcriptional start site. The genomic structure of mouse Cyp1 ...[more]

PMID: 19026991

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Project description:The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates the biological and toxicological effects of halogenated aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). When activated by dioxin, the cytosolic AhR protein complex translocates into the nucleus and dimerizes with the ARNT (Ah receptor nuclear translocator) protein. The heteromeric ligand:AhR/Arnt complex then recognizes and binds to its specific DNA recognition site, the dioxin response element (DRE). DREs are located upstream of cytochrome P4501A1 (CYP1A1) and other AhR-responsive genes, and binding of the AhR complex stimulates their transcription. Although CYP1A1 expression has been used as the model system to define the biochemical and molecular mechanism of AhR action, there is still limited knowledge about the roles of each of the seven DREs located in the CYP1A1 promoter. These seven DREs are conserved in mouse, human and rat. Deletion analysis showed that a single DRE at -488 was enough to activate the transcription. Truncation analysis demonstrated that the DRE at site -981 has the highest transcriptional efficiency in response to TCDD. This result was verified by mutation analysis, suggesting that the conserved DRE at site -981 could represent a significant and universal AhR regulatory element for CYP1A1. The reversed substituted intolerant core sequence (5'-GCGTG-3' or 5'-CACGC-3') of seven DREs reduced the transcriptional efficiency, which illustrated that the adjacent sequences of DRE played a vital role in activating transcription. The core DRE sequence (5'-TNGCGTG-3') tends to show a higher transcriptional level than that of the core DRE sequence (5'-CACGCNA-3') triggered by TCDD. Furthermore, in the core DRE (5'-TNGCGTG-3') sequence, when "N" is thymine or cytosine (T or C), the transcription efficiency was stronger compared with that of the other nucleotides. The effects of DRE orientation, DRE adjacent sequences and the nucleotide "N" in the core DRE (5'-TNGCGTG-3') sequence on the AhR-regulated CYP1A1 transcription in response to TCDD were studied systematically, and our study laid a good foundation for further investigation into the AhR-dependent transcriptional regulation triggered by dioxin and dioxin-like compounds.

Dataset Information

Conserved genomic structure of the Cyp1a1 and Cyp1a2 loci and their dioxin responsive elements cluster.

Publications

Conserved genomic structure of the Cyp1a1 and Cyp1a2 loci and their dioxin responsive elements cluster.

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