A NOVEL DISTAL ENHANCER CONFERS CHORIONIC EXPRESSION ON THE HUMAN RENIN GENE

Renin catalyzes the rate-limiting step of the renin-angiotensin system , which regulates blood pressure and electrolyte homeostasis. To deter mine cell-specific human renin gene control elements, the transcriptio nal activity of promoter regions up to position -8876 was studied in r enin-expressing cells. A positive regulatory region conferring similar to 57-fold higher transcriptional activity to the human renin gene pr omoter in chorionic cells was identified between nucleotides -5777 and -5552, It had the orientation-independent activity typical of classic al enhancers. It also conferred similar to 59-fold higher transcriptio nal levels from the heterologous simian virus 40 (SV40) promoter in ch orionic cells and similar to 6-fold higher transcriptional levels in C alu-6 and As4.1 cells, whereas no effect was measured in non-renin-exp ressing cells. DNase I footprinting showed that this enhancer contains three binding sites for chorionic cell nuclear extracts. Functional a nalysis suggested that the activity of the enhancer is regulated by di fferential mechanisms in the three renin-expressing cells involving a complex arrangement of AP-1 motifs binding cell-specific members of th e basic leucine zipper family of transcription factors. Thus, our resu lts demonstrate that this enhancer plays a key role in the expression of the human renin gene in the chorion and may also be involved in its regulated expression in other tissues.