Cell-type-specific and hypoxia-inducible expression of the human erythropoietin gene in transgenic mice.

Synthesis of erythropoietin, the primary humoral regulator of erythropoiesis, in liver and kidney is inducible by anemia or hypoxia. Analysis of human erythropoietin gene expression in transgenic mice revealed that sequences located 6-14 kilobases 5' to the gene direct expression to the kidney, whereas sequences within the immediate 3'-flanking region control hepatocyte-specific expression. Human erythropoietin transcription initiation sites were differentially utilized in liver and kidney.

Hypoxia-inducible nuclear factors bind to an enhancer element located 3' to the human erythropoietin gene.

Human erythropoietin gene expression in liver and kidney is inducible by anemia or hypoxia. DNase I-hypersensitive sites were identified 3' to the human erythropoietin gene in liver nuclei. A 256-base-pair region of 3' flanking sequence was shown by DNase I protection and electrophoretic mobility-shift assays to bind four or more different nuclear factors, at least two of which are induced by anemia in both liver and kidney, and the region functioned as a hypoxia-inducible enhancer in transient expression assays.