title: Repression via the GATA box is essential for tissue-specific erythropoietin gene expression.
abstract: In response to anemia, erythropoietin (Epo) gene transcription is markedly induced in the kidney and liver. To elucidate how Epo gene expression is regulated in vivo, we established transgenic mouse lines expressing green fluorescent protein (GFP) under the control of a 180-kb mouse Epo gene locus. GFP expression was induced by anemia or hypoxia specifically in peritubular interstitial cells of the kidney and hepatocytes surrounding the central vein. Surprisingly, renal Epo-producing cells had a neuronlike morphology and expressed neuronal marker genes. Furthermore, the regulatory mechanisms of Epo gene expression were explored using transgenes containing mutations in the GATA motif of the promoter region. A single nucleotide mutation in this motif resulted in constitutive ectopic expression of transgenic GFP in renal distal tubules, collecting ducts, and certain populations of epithelial cells in other tissues. Since both GATA-2 and GATA-3 bind to the GATA box in distal tubular cells, both factors are likely to repress constitutively ectopic Epo gene expression in these cells. Thus, GATA-based repression is essential for the inducible and cell type-specific expression of the Epo gene.
authors.affiliation: Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Obara
authors.forename: Norio
authors.initials: N
authors.lastname: Suzuki
authors.forename: Kibom
authors.initials: K
authors.lastname: Kim
authors.forename: Toshiro
authors.initials: T
authors.lastname: Nagasawa
authors.forename: Shigehiko
authors.initials: S
authors.lastname: Imagawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D020816:Amino Acid Motifs; D000740:Anemia; D000818:Animals; D004921:Erythropoietin / Q000235:genetics*; D050989:GATA2 Transcription Factor / Q000502:physiology*; D050990:GATA3 Transcription Factor / Q000502:physiology*; D005786:Gene Expression Regulation; D000860:Hypoxia; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology; D011401:Promoter Regions, Genetic / Q000502:physiology*; D014018:Tissue Distribution
chemical_list: D050989:GATA2 Transcription Factor; D050990:GATA3 Transcription Factor; D004921:Erythropoietin