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Molecular and Cellular Biology, November 1998, p. 6634-6640, Vol. 18, No. 11
Hematopoiesis Section, Genetics and Molecular
Biology Branch, National Human Genome Research Institute, National
Institutes of Health, Bethesda, Maryland1;
Yale University, New Haven,
Connecticut2; and
University of
Washington, Seattle, Washington3
Received 18 May 1998/Returned for modification 6 July 1998/Accepted 23 July 1998
During development, changes occur in both the sites of
erythropoiesis and the globin genes expressed at each developmental stage. Previous work has shown that high-level expression of human
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Copyright © 1998, American Society for Microbiology. All rights reserved.
Substitution of the Human
-Spectrin Promoter for
the Human A
-Globin Promoter Prevents Silencing of a
Linked Human
-Globin Gene in Transgenic Mice
-like globin genes in transgenic mice requires the
presence of the locus control region (LCR). Models of hemoglobin
switching propose that the LCR and/or stage-specific elements interact
with globin gene sequences to activate specific genes in erythroid cells. To test these models, we generated transgenic mice which contain
the human A
-globin gene linked to a 576-bp fragment
containing the human
-spectrin promoter. In these mice, the
-spectrin A
-globin (
sp/A
) transgene
was expressed at high levels in erythroid cells throughout development.
Transgenic mice containing a 40-kb cosmid construct with the micro-LCR,
sp/A
-, 
-,
-, and
-globin genes showed no
developmental switching and expressed both human
- and
-globin
mRNAs in erythroid cells throughout development. Mice containing
control cosmids with the A
-globin gene promoter showed
developmental switching and expressed A
-globin mRNA in
yolk sac and fetal liver erythroid cells and
-globin mRNA in fetal
liver and adult erythroid cells. Our results suggest that replacement
of the
-globin promoter with the
-spectrin promoter allows
the expression of the
-globin gene. We conclude that the
-globin
promoter is necessary and sufficient to suppress the expression of the
-globin gene in yolk sac erythroid cells.
*
Corresponding author. Mailing address: Hematopoiesis
Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Building 49, Room
3A14 MSC 4442, Bethesda, MD 20892-4442. Phone: (301) 402-0902. Fax:
(301) 402-4929. E-mail: tedyaz{at}nhgri.nih.gov.
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