Position-independent, aberrant expression of the human ornithine decarboxylase gene in transgenic mice

Abstract

We have generated transgenic mouse lines carrying the human ornithine decarboxylase (ODC) gene in their genome. Six of 7 transgenic lines overexpressed ODC in most of their tissues, which was most strikingly manifested as a highly ectopic enzyme activity in the testis and brain of transgenic mice. A close correlation existed between enzyme activity (or ODC mRNA level) and gene copy number in testis and brain, indicating that the expression occurred independently of the transgene's chromosomal integration site. Transgenic mice carrying the mouse ODC promoter fused to the bacterial chloramphenicol acetyltransferase gene expressed the reporter gene in a similarly aberrant fashion. Even though the human ODC gene construct contained 5'-flanking sequences (800 nt), sufficient to confer maximal promoter activity in transfected cells, and about 1000 nt of 3'-flanking DNA, it is improbable that the observed gene copy number-dependent expression was due to the presence of so-called DNA attachment elements. In contrast, our data suggest that expression of the mammalian ODC gene is governed by distal silencer elements that were missing in the transgene constructs, which permitted an apparently position-independent expression of the transgene.