Alternative promoters determine tissue-specific expression profiles of the human microsomal epoxide hydrolase gene (EPHX1)

Shun Hsin Liang, Christopher Hassett, Curtis J. Omiecinski

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Abstract

Microsomal epoxide hydrolase (EPHX1) catalyzes hydration reactions that determine the cellular disposition of reactive epoxide derivatives. Whereas the previously defined EPHX1 exon 1 sequence (E1) is derived from a promoter proximal to exon 2 of the EPHX1 coding region, in this investigation, we identified an alternative EPHX1 exon 1 sequence, E1-b, originating from a gene promoter localized ∼18.5 kb upstream of exon 2. Northern hybridizations demonstrated that the E1-b variant is widely expressed and that the E1-b promoter functions as the primary driver of EPHX1 expression in human tissues. In contrast, the E1 promoter directs expression only in the liver. To examine the basis for liver-specific usage of the E1 promoter, we identified several potential cis-regulatory elements that included GATA (-110/-105) and hepatocyte nuclear factor 3 (HNF3) (-96/ -88) motifs. GATA-4 was the principal GATA family member interacting with its respective motif, whereas both HNF3α and HNF3β were capable of interacting with the HNF3 element. GATA-4 and HNF3α/HNF3β DNA binding complexes were enriched in hepatic cells. Site-directed mutagenesis and transactivation analyses of the E1 promoter revealed that GATA-4 is probably a principal factor that regulates liver-specific expression of the E1 variant, with HNF3α and HNF3β acting to negatively regulate GATA-4 function in hepatic cells.

Original languageEnglish (US)
Pages (from-to)220-230
Number of pages11
JournalMolecular pharmacology
Volume67
Issue number1
DOIs
Publication statusPublished - Jan 1 2005

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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