A role for the distal CCAAT box of the gamma-globin gene in Hb switching.
Hereditary persistence of fetal hemoglobin (HPFH) is a condition manifested by continued expression of the gamma-globin gene in adult life. The four types of HPFH mutations (-117 G-A, -114 C-T, -114 C-G, and 13 bp del) clustered in the vicinity of the distal CCAAT box of the gamma-globin gene suggest the relevance of this region to the fetal-to-adult hemoglobin switching. Functional analysis in erythroid cell lines showed that these HPFH mutations reduced the activity of the gamma-globin promoter in K562 expressing embryonic and fetal globin chains, but not in KU812 expressing fetal and adult globin chains. These results suggest that the distal CCAAT box region has different functions in the fetus and the adult. In vitro, binding of NFE3 to the distal CCAAT box was commonly reduced by these HPFH mutations, suggesting that the binding of NFE3 to the distal CCAAT box may repress the gamma-globin gene in adults. Overlap of the binding sites of NFE3 and CP1, a potential activator, indicates the regulation of the gamma-globin gene by the competition between these factors. In addition, an unknown factor interacting with the -114 C-T HPFH mutant CCAAT box may be involved in elevation of the gamma-globin expression in an individual with the -114 C-T mutation.
Katsube
T
T
Institute of Genetic Information, Kyushu University, Fukuoka.
Fukumaki
Y
Y
D001483:Base Sequence; D002460:Cell Line; D015672:Erythroid Precursor Cells / Q000502:physiology; D005319:Fetal Hemoglobin / Q000235:genetics*; D005812:Genes, Switch; D005914:Globins / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009838:Oligodeoxyribonucleotides / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation
D009838:Oligodeoxyribonucleotides; D005914:Globins; D005319:Fetal Hemoglobin