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A novel regulatory element of the human alpha-globin gene responsible for its constitutive expression 总被引:3,自引:0,他引:3
The alpha-globin gene is expressed at a constitutively high level upon gene transfer into both erythroid and nonerythroid cells. The beta-globin gene, on the other hand, is dependent on the presence of a linked viral enhancer for its efficient expression upon transfer into heterologous cells. In this report, we describe a novel regulatory element within the structural alpha-globin gene which can activate its own promoter to result in a high level of expression in both erythroid and non-erythroid cells. This regulatory element does not appear to have the properties of a classical enhancer. While this element exerts a positive effect on its own promoter, we have demonstrated in a previous study that the same element exerts a negative effect on heterologous genes such as the beta- and gamma-globin genes. In this study, we localize this element to a 259 nucleotide fragment immediately downstream from the translation initiation codon which is partially overlapped by a DNase I hypersensitive domain only in erythroid cells. We propose that this element may activate the alpha-globin gene promoter in all cell types in vivo as it does in vitro. The specificity of erythroid expression of the alpha-globin gene in vivo is probably determined by a "permissive" chromatin configuration in erythroid cells and a "nonpermissive" configuration in non-erythroid cells. 相似文献
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N Raich V Mignotte A Dubart D Beaupain P Leboulch M Romana C Chabret P Charnay T Papayannopoulou M Goossens 《The Journal of biological chemistry》1989,264(17):10186-10192
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alpha-thalassaemia is an inherited blood disorder caused by a decrease in the synthesis of alpha-globin due to mutations in one or both of the alpha-globin genes located on human chromosome 16. A 191 kb transgene derived from a sequenced bacterial artificial chromosome (BAC) clone carrying the human alpha-globin gene cluster, together with about 100 kb of sequence upstream of DNase1 hypersensitive site HS-40 and 30 kb downstream of the alpha1-globin gene, was introduced into fertilised mouse oocytes by pronuclear microinjection. Three transgenic founder mice were obtained. Analysis of one transmitting line by fluorescent in situ hybridisation and quantitative PCR demonstrated a single copy integration of the human alpha-globin transgene on chromosome 1. Analysis of haemoglobins from the peripheral blood by cellulose acetate electrophoresis and high performance liquid chromatography (HPLC) demonstrated synthesis of human alpha-globin to about 36% of the level of each mouse alpha-globin locus. Breeding of transgenic mice with mice heterozygous for a knockout (KO) deletion of both murine alpha-globin genes showed that the human alpha-globin locus restored haemoglobin levels and red cell distribution width to normal in double heterozygous mice and significantly normalised other haematological parameters. Interestingly the human transgene also induced a significant increase in red cell production and haematocrit above wild type values. This is the first report demonstrating complementation of a murine alpha-globin KO mutation by human alpha-globin gene expression from an intact human alpha-globin locus. The transgenic mouse model described in this report should be very useful for the study of human alpha-globin gene regulation and for the development of strategies to down regulate alpha-globin production as a means of ameliorating the severity of beta-thalassaemia. 相似文献
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The Epstein-Barr virus (EBV) early promoter DR contains a cis-acting element responsive to the EBV transactivator EB1 and an enhancer with constitutive and inducible activities. 总被引:19,自引:15,他引:4
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P Chavrier H Gruffat A Chevallier-Greco M Buisson A Sergeant 《Journal of virology》1989,63(2):607-614
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