The influence of chromosomal location on the expression of two transgenes in mice

We have generated mice having a single copy of the human haptoglobin gene (Hp(2)), driven by its natural promoter, and a neomycin resistance gene (Neo), driven by a herpes simplex thymidine kinase promoter with polyoma enhancers, inserted into two defined chromosomal locations, the Hprt locus on the X-chromosome and the apolipoprotein (apo) AI-CIII gene cluster on chromosome 9. The haptoglobin promoter is highly specialized in its tissue of action; the viral promoter has few restrictions. The apoAI-CIII gene is naturally active in only two tissues, whereas the Hprt gene region is ubiquitously active. Expression of both transgenes at substantial levels was achieved only (a) when the transgenes were inserted into the genome close to a known tissue-specific enhancer/locus control region in the apoAI-CIII gene cluster, and (b) when known conditions for function of their promoters were met. The specificities of the two chromosomal regions and of the two promoters are preserved, but their interactions are not specific. Ne conclude that transgenes are affected by locus-related enhancers in the same manner as nearby endogenous genes. Our experiments reinforce the usefulness of using gene targeting to direct single-copy transgenes to appropriate chromosomal locations.