Regulation of erythroid-specific gene expression.
The aim of our group's work has been to elucidate how the alpha- and beta-globin genes come to be co-expressed together with a set of characteristic non-globin genes during erythroid cell differentiation. Our most significant progress concerns the identification and analysis of a species-conserved transcription factor, EF1, that appears to play a general role in the regulation of erythroid-specific gene transcription. We have shown that the 4 kb of 5' flanking region of the mouse alpha-globin gene contains two erythroid-specific cis-control elements, both of which involve EF1 binding sites. We have also identified functionally active EF1 binding sites in the mouse beta-globin promoter, as well as in the erythroid-specific promoter of the gene encoding the haem biosynthetic enzyme, porphobilinogen deaminase (PBG-D). The function of the PBG-D promoter depends in part on the cooperation between an EF1 binding site and an adjacent CACCC motif, this being abolished if their spacing is increased beyond 40 nt. We have also investigated the mechanisms involved in the up-regulation in erythroid cells of two non-globin genes we have cloned, encoding the RBC-specific lipoxygenase (LOX) and glutathione peroxidase (GSHPX). As judged by the presence of tissue-specific DNAse I hypersensitive sites, the tissue-specific regulation of the GSHPX gene seems to be due to regulatory regions 3' to the gene. The level of GSHPX is also regulated by selenium and this occurs at two levels: during mRNA formation, and during translation of the mRNA due to the regulation of selenocysteine incorporation specified by a unusual use of the UGA codon.(ABSTRACT TRUNCATED AT 250 WORDS)
Harrison
P R
PR
Beatson Institute for Cancer Research, Bearsden, Glasgow, Scotland.
Plumb
M
M
Frampton
J
J
Thiele
B
B
Macleod
K
K
Chester
J
J
Chambers
I
I
Fleming
J
J
O'Prey
J
J
Walker
M
M
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D004912:Erythrocytes / Q000166:cytology*; D005786:Gene Expression Regulation; D005914:Globins / Q000096:biosynthesis / Q000235:genetics*; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000235:genetics; D008084:Lipoxygenase / Q000235:genetics; D008969:Molecular Sequence Data
D005914:Globins; D005979:Glutathione Peroxidase; D008084:Lipoxygenase