title: Lethal beta-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF.
abstract: Globin genes are regulated in a tissue-specific and developmental stage-specific manner, with the beta-globin gene being the last to be activated in the beta-gene cluster. CACCC-nucleotide sequences, which bind multiple nuclear proteins, including ubiquitously expressed Sp1 and erythroid Krüppel-like factor (EKLF), are among the cis-regulatory sequences critical for transcription of globin and non-globin erythroid-expressed genes. To determine the function of EKLF in vivo, we created mice deficient in EKLF by gene targeting. These embryos die of anaemia during fetal liver erythropoiesis and show the molecular and haematological features of beta-globin deficiency, found in beta-thalassaemia. Although it is expressed at all stages, EKLF is not required for yolk sac erythropoiesis, erythroid commitment or expression of other potential target genes. Its stage-specific and beta-globin-gene-specific requirement suggests that EKLF may facilitate completion of the fetal-to-adult (haemoglobin gamma to beta) switch in humans.
authors.affiliation: Division of Hematology/oncology, Children's Hospital, Boston, Massachusetts, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Perkins
authors.forename: A H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: S H
authors.initials: SH
authors.lastname: Orkin
mesh_terms: D000740:Anemia / Q000209:etiology; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004247:DNA; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004530:Egg Yolk / Q000166:cytology; D004920:Erythropoiesis / Q000235:genetics; D005260:Female; D005313:Fetal Death; D018390:Gene Targeting; D005812:Genes, Switch; D005914:Globins / Q000172:deficiency / Q000235:genetics; D051741:Kruppel-Like Transcription Factors; D008099:Liver / Q000166:cytology / Q000196:embryology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D016335:Zinc Fingers / Q000235:genetics; D017086:beta-Thalassemia / Q000209:etiology*
chemical_list: D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; C080774:erythroid Kruppel-like factor; D005914:Globins; D004247:DNA