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First published on September 4, 2007; DOI: 10.1124/mol.107.039826

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Received for publication July 19, 2007.
Revised August 14, 2007.
Accepted for publication September 4, 2007.

A dioxin-responsive enhancer 3' of the human CYP1A2 gene

Steven T Okino 1, Linda C. Quattrochi 2, Deepa Pookot 1, Mieko Iwahashi 2, Rajvir Dahiya 1*

1 San Francisco Veterans Affairs Medical Center 2 University of Colorado Health Science Center

* Address correspondence to: E-mail: rdahiya{at}urology.ucsf.edu

Abstract

The human CYP1A genes, CYP1A1 and CYP1A2, are in a head-to-head orientation on chromosome 15. Both CYP1A genes, as well as CYP1B1, are transcriptionally induced by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that binds 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin). Although the TCDD-responsive enhancers for CYP1A1 and CYP1B1 are well characterized, a similar CYP1A2 enhancer has not been identified. In the human prostate cell line RWPE-1, CYP1A2 mRNA expression is dramatically induced by TCDD. Therefore, analysis of the native CYP1A2 gene in these cells can provide insight into its induction mechanism. To identify sites that may bind AhR on the CYP1A locus we scanned 75 kb of chromosome 15 sequence for high affinity AhR binding sites. We then analyzed most of the sites for TCDD-inducible AhR interaction by chromatin immunoprecipitation. As expected, the CYP1A1 and CYP1B1 enhancers bind AhR in TCDD-treated cells. Importantly, we identify a region 3' of CYP1A2 that binds AhR in response to TCDD. We cannot detect AhR binding at other sites on the CYP1A locus. In vivo footprinting demonstrates that two AhR binding sites in CYP1A2's 3' region are occupied in TCDD-treated cells. Reporter-gene studies show that these sites confer TCDD-responsiveness to a heterologous promoter. AhR also binds to CYP1A2's 3' region in TCDD-treated LS180 cells, but not in HepG2 and ND-1 cells. In the latter cell lines CYP1A2's 3' region is extensively methylated. In summary, we identify a novel TCDD-responsive enhancer for CYP1A2. Surprisingly, this enhancer is not conserved across species and is primarily human-specific.


Key words: Cytochrome P450, Regulation - transcriptional, Regulation - xenobiotic, Ah receptor


This article has been cited by other articles:


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MicroRNA-373 induces expression of genes with complementary promoter sequences
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[Abstract] [Full Text] [PDF]


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