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Regulated basal, inducible, and tissue-specific human erythropoietin gene
expression in transgenic mice requires multiple cis DNA sequences
A Madan, C Lin, SL Hatch and PT Curtin
Department of Pediatrics, University of California, San Francisco, USA.
Erythropoietin (Epo) gene expression in kidney and liver is inducible by
anemia. To localize the sequences necessary for regulated expression of the
Epo gene, we constructed transgenic mice containing five human Epo gene
constructs and examined Epo expression under basal conditions and with
anemia. Mice containing the Epo gene with 0.3 kb of 5' flanking sequence,
0.7 kb of 3' flanking sequence, and either all introns or only intron I
alone were polycythemic, had Epo expression in various tissues (including
non-Epo-producing tissues), and induction only in liver. In contrast, mice
containing the Epo gene with 8.5 kb of 3' flanking sequence and either 9.5
or 22 kb of 5' flanking sequence had basal expression at low levels in
appropriate tissues and were less likely to be markedly polycythemic. Mice
with the smaller of these two constructs had induction only in the liver,
whereas those with the larger construct had induction in the kidney and
liver. These studies indicate that sequences sufficient for induction in
the liver are located in close proximity to the Epo gene, including the
immediate 5' and 3' flanking sequence and the first intron. They also
indicate that sequences required for induction in the kidney are located
more than 9.5 kb 5' to the gene. Furthermore, comparison of these and prior
transgenic studies suggest that sequences that limit the basal expression
of the Epo gene are located downstream of the gene. We conclude that
multiple cis DNA sequences are required for regulated Epo gene expression.
Volume 85,
Issue 10,
pp. 2735-2741,
05/15/1995
Copyright © 1995 by The American Society of Hematology
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