scholarly journals Regulation of human alpha-globin gene expression and alpha-thalassemia

2008 ◽  
Vol 7 (4) ◽  
pp. 1045-1053 ◽  
Author(s):  
D.M. Ribeiro ◽  
M.F. Sonati
Keyword(s):  
Gene Expression ◽  
Globin Gene ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Globin Gene Expression

scholarly journals Alpha-thalassemia resulting from deletion of regulatory sequences far upstream of the alpha-globin structural genes

Blood ◽  
1991 ◽  
Vol 78 (6) ◽  
pp. 1589-1595
Author(s):  
L Romao ◽  
L Osorio-Almeida ◽  
DR Higgs ◽  
J Lavinha ◽  
SA Liebhaber
Keyword(s):  
Gene Expression ◽  
Transcription Start Site ◽  
Globin Gene ◽  
Regulatory Sequences ◽  
Start Site ◽  
Structural Genes ◽  
Transcription Start ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Globin Gene Expression

We describe an alpha-thalassemia determinant in which alpha-globin expression is silenced by a deletion located 27 kb 5′ to the transcription start site of the alpha 2-globin gene. This alpha- thalassemic determinant, (alpha alpha)MM, is a member of a newly described group of thalassemic mutations resulting from deletion of locus-controlling sequences critical to globin gene expression.

scholarly journals Human embryonic zeta-globin gene expression in mouse-human hybrid erythroid cell lines

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 1212-1217 ◽  
Author(s):  
HY Luo ◽  
AB Deisseroth ◽  
DH Chui
Keyword(s):  
Gene Expression ◽  
Globin Gene ◽  
Erythroid Cell ◽  
Hybrid Cells ◽  
Globin Chains ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Zeta Globin Gene ◽  
Murine Erythroleukemia ◽  
Globin Gene Expression

Abstract The human alpha-globin-like embryonic zeta-globin chains are present in abundance during the first 5 to 6 weeks of gestation. Subsequently, zeta-globin chains are present in fetal blood at a very low level, which is supplanted by the expression of alpha-globin chains. Adult individuals who are carriers of the (--SEA/) alpha-thalassemia deletion, in contrast to normal adults, have low levels of embryonic zeta-globin chains in their circulating erythrocytes. In this investigation, we constructed stable mouse-human hybrid cells with murine erythroleukemia cells bearing human chromosome 16, with either the normal alpha-globin gene cluster (alpha alpha/) or the (--SEA/) type of alpha-thalassemia deletion. The results on the human zeta- globin gene expression in these hybrid cells indicate that murine adult erythroid transcription factors can induce the expression of human embryonic zeta-globin gene is cis to the (--SEA/) deletion, in parallel with the endogenous mouse alpha-globin gene expression. These data also show the importance of the DNA sequences within the (--SEA) deletion in regulating the expression of zeta-globin gene in cis during normal human hemoglobin ontogeny.

scholarly journals Human embryonic zeta-globin gene expression in mouse-human hybrid erythroid cell lines

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 1212-1217 ◽  
Author(s):  
HY Luo ◽  
AB Deisseroth ◽  
DH Chui
Keyword(s):  
Gene Expression ◽  
Globin Gene ◽  
Erythroid Cell ◽  
Hybrid Cells ◽  
Globin Chains ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Zeta Globin Gene ◽  
Murine Erythroleukemia ◽  
Globin Gene Expression

The human alpha-globin-like embryonic zeta-globin chains are present in abundance during the first 5 to 6 weeks of gestation. Subsequently, zeta-globin chains are present in fetal blood at a very low level, which is supplanted by the expression of alpha-globin chains. Adult individuals who are carriers of the (--SEA/) alpha-thalassemia deletion, in contrast to normal adults, have low levels of embryonic zeta-globin chains in their circulating erythrocytes. In this investigation, we constructed stable mouse-human hybrid cells with murine erythroleukemia cells bearing human chromosome 16, with either the normal alpha-globin gene cluster (alpha alpha/) or the (--SEA/) type of alpha-thalassemia deletion. The results on the human zeta- globin gene expression in these hybrid cells indicate that murine adult erythroid transcription factors can induce the expression of human embryonic zeta-globin gene is cis to the (--SEA/) deletion, in parallel with the endogenous mouse alpha-globin gene expression. These data also show the importance of the DNA sequences within the (--SEA) deletion in regulating the expression of zeta-globin gene in cis during normal human hemoglobin ontogeny.

scholarly journals Alpha-thalassemia resulting from deletion of regulatory sequences far upstream of the alpha-globin structural genes

Blood ◽  
1991 ◽  
Vol 78 (6) ◽  
pp. 1589-1595 ◽  
Author(s):  
L Romao ◽  
L Osorio-Almeida ◽  
DR Higgs ◽  
J Lavinha ◽  
SA Liebhaber
Keyword(s):  
Gene Expression ◽  
Transcription Start Site ◽  
Globin Gene ◽  
Regulatory Sequences ◽  
Start Site ◽  
Structural Genes ◽  
Transcription Start ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Globin Gene Expression

Abstract We describe an alpha-thalassemia determinant in which alpha-globin expression is silenced by a deletion located 27 kb 5′ to the transcription start site of the alpha 2-globin gene. This alpha- thalassemic determinant, (alpha alpha)MM, is a member of a newly described group of thalassemic mutations resulting from deletion of locus-controlling sequences critical to globin gene expression.

scholarly journals Targeted inactivation of the major positive regulatory element (HS-40) of the human alpha-globin gene locus

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 1202-1211 ◽  
Author(s):  
A Bernet ◽  
S Sabatier ◽  
DJ Picketts ◽  
R Ouazana ◽  
F Morle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Locus ◽  
Regulatory Element ◽  
Globin Gene ◽  
Marker Gene ◽  
Regulatory Elements ◽  
Target System ◽  
Flp Recombinase ◽  
Alpha Globin ◽  
Globin Gene Expression

Abstract We have examined the role of the major positive upstream regulatory element of the human alpha-globin gene locus (HS-40) in its natural chromosomal context. Using homologous recombination, HS-40 was replaced by a neo marker gene in a mouse erythroleukemia hybrid cell line containing a single copy of human chromosome 16. In clones from which HS-40 had been deleted, human alpha-globin gene expression was severely reduced, although basal levels of alpha 1 and alpha 2-globin mRNA expression representing less than 3% of the level in control cell lines were detected. Deletion of the neo marker gene, by using FLP recombinase/FLP recombinase target system, proved that the phenotype observed was not caused by the regulatory elements of this marker gene. In the targeted clones, deletion of HS-40 apparently does not affect long-range or local chromatin structure at the alpha promoters. Therefore, these results indicate that, in the experimental system used, HS-40 behaves as a strong inducible enhancer of human alpha- globin gene expression.

scholarly journals Role of upstream DNase I hypersensitive sites in the regulation of human alpha globin gene expression

Blood ◽  
1993 ◽  
Vol 82 (5) ◽  
pp. 1666-1671
Author(s):  
JA Sharpe ◽  
RJ Summerhill ◽  
P Vyas ◽  
G Gourdon ◽  
DR Higgs ◽  
...  
Keyword(s):  
Gene Expression ◽  
Globin Gene ◽  
Single Copy ◽  
Beta Globin ◽  
Hypersensitive Sites ◽  
Alpha Globin ◽  
Alpha Gene ◽  
High Level ◽  
Globin Gene Expression

Erythroid-specific DNase 1 hypersensitive sites have been identified at the promoters of the human alpha-like genes and within the region from 4 to 40 kb upstream of the gene cluster. One of these sites, HS-40, has been shown previously to be the major regulator of tissue-specific alpha-globin gene expression. We have now examined the function of other hypersensitive sites by studying the expression in mouse erythroleukemia (MEL) cells of various fragments containing these sites attached to HS-40 and an alpha-globin gene. High level expression of the alpha gene was observed in all cases. When clones of MEL cells bearing a single copy of the alpha-globin gene fragments were examined, expression levels were similar to those of the endogenous mouse alpha genes and similar to MEL cells bearing beta gene constructs under the control of the beta-globin locus control region. However, there was no evidence that the additional hypersensitive sites increased the level of expression or conferred copy number dependence on the expression of a linked alpha gene in MEL cells.

Amplification and expression of human alpha-globin genes in Chinese hamster ovary cells

1984 ◽  
Vol 4 (8) ◽  
pp. 1469-1475
Author(s):  
Y F Lau ◽  
C C Lin ◽  
Y W Kan
Keyword(s):  
Gene Expression ◽  
Gene Amplification ◽  
Chinese Hamster Ovary ◽  
Chinese Hamster Ovary Cells ◽  
Globin Gene ◽  
Chinese Hamster ◽  
Globin Genes ◽  
Ovary Cells ◽  
Alpha Globin ◽  
Globin Gene Expression

We studied the effects of gene amplification on human globin gene expression in Chinese hamster ovary cells. The normal human alpha-globin gene (N alpha 2) and a hybrid gene (M alpha G) containing the 5' promoter-regulator region of the mouse metallothionein gene and the human structural alpha 2-globin gene were linked to a modular SV2-cDNA dihydrofolate reductase (DHFR) gene. The recombinant DNA molecules were introduced into Chinese hamster ovary cells by calcium phosphate precipitation. After initial selection to retain the DHFR and linked sequences, the cells were cultured in increasing concentrations of methotrexate up to 0.2 mM. Southern blot analysis of total cellular DNA showed an approximately 500- to 1,000-fold increase in the number of copies of DHFR and human alpha-globin genes. The transcription of the alpha-globin and DHFR genes increased as their copy number within the cells increased. The transcription of the amplified hybrid M alpha G gene was also inducible with cadmium treatments. Both mature mRNA and "read-through" transcripts were observed. DHFR constituted approximately 10% of pulse-labeled cellular proteins in these cells, but no human alpha-globin was detected. In vitro translation of polyadenylated RNA from these cells showed that alpha-globin mRNA transcribed from the amplified alpha-globin genes was functional and directed alpha-globin chain synthesis. In situ hybridization of 3H-labeled alpha-globin and DHFR DNA probes in chromosome preparations from the two cell lines indicated that both genes were coamplified in the same chromosomal locations in each cell type. These results indicate that gene amplification enhances human globin gene expression in cultured Chinese hamster ovary cells.

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