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Molecular and Cellular Biology, November 1998, p. 6634-6640, Vol. 18, No. 11
0270-7306/98/$04.00+0
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

Denise E. Sabatino,¹ Amanda P. Cline,¹ Patrick G. Gallagher,² Lisa J. Garrett,¹ George Stamatoyannopoulos,³ Bernard G. Forget,² and David M. Bodine^1,*

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 -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.

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^* 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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Molecular and Cellular Biology, November 1998, p. 6634-6640, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

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