Human uroporphyrinogen-III synthase: Genomic organization, alternative promoters, and erythroid-specific expression

Uroporphyrinogen-III (URO) synthase is the heme biosynthetic enzyme defecti ve in congenital erythropoietic porphyria. The similar to 34-kb human URO-s ynthase gene (UROS) was isolated, and its organization and tissue-specific expression were determined. The gene had two promoters that generated house keeping and erythroid-specific transcripts with unique 5'-untranslated sequ ences (exons 1 and 2A) followed by nine common coding exons (2B to 10). Exp ression arrays revealed that the housekeeping transcript was present in all tissues, while the erythroid transcript was only in erythropoietic tissues . The housekeeping promoter lacked TATA and SP1 sites, consistent with the observed low level expression in most cells, whereas the erythroid promoter contained GATA1 and NF-ES sites for erythroid specificity. Luciferase repo rter assays demonstrated that the housekeeping promoter was active in both erythroid K562 and HeLa cells, while the erythroid promoter was active only in erythroid cells and its activity was increased during hemin-induced ery throid differentiation. Thus, human URO-synthase expression is regulated du ring erythropoiesis by an erythroid-specific alternative promoter. (C) 2000 Academic Press.