title: Increased gamma-globin expression in a nondeletion HPFH mediated by an erythroid-specific DNA-binding factor.
abstract: In man, a shift from gamma- to beta-globin gene expression in erythroblasts underlies a switch from fetal to adult haemoglobin during development. In hereditary persistence of fetal haemoglobin (HPFH), inappropriately high gamma-globin expression in adult life is associated with deletions in the beta-globin cluster or with single-base changes upstream of the gamma-globin genes. To account for enhanced gamma-gene expression in HPFH of the non-deletion type, we tested the nuclear proteins of human erythroleukaemia cells that bind gamma-promoter sequences in vitro by correlating specific mutations in their binding sites with promoter activity. An erythroid-specific factor (GF-1) binds as a single molecule to the -195 to -170 region and contacts two TATCT(AGATA) motifs, but not the conserved octamer (ATGCAAAT) that separates them. We observe that a single change (at -175, T----C) found in HPFH leads to increased promoter activity only in erythroid cells. This effect is mediated by GF-1, the human counterpart of the chicken erythroid factor Eryf 1. The form of HPFH we studied here is an inherited disorder which can be ascribed to the action of a cell-specific DNA-binding factor on a mutant promoter.
authors: Division of Hematology-Oncology, Children's Hospital, Boston, Massachusetts.
authors: D I
authors: DI
authors: Martin
authors: S F
authors: SF
authors: Tsai
authors: S H
authors: SH
authors: Orkin
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics*; D050981:Erythroid-Specific DNA-Binding Factors; D005319:Fetal Hemoglobin / Q000235:genetics*; D005914:Globins / Q000235:genetics*; D006453:Hemoglobinopathies / Q000235:genetics*; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics; D011401:Promoter Regions, Genetic; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D014157:Transcription Factors; D005914:Globins; D005319:Fetal Hemoglobin