Substitution of the Human beta -Spectrin Promoter for the Human Agamma -Globin Promoter Prevents Silencing of a Linked Human beta -Globin Gene in Transgenic Mice

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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 $beta$ -Spectrin Promoter for the Human ^A $gamma$ -Globin Promoter Prevents Silencing of a Linked Human $beta$ -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. Bodine¹^,^*

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 developmentalstage. Previous work has shown that high-level expression of human $beta$ -like globin genes in transgenic mice requires the presence ofthe locus control region (LCR). Models of hemoglobin switchingpropose that the LCR and/or stage-specific elements interact withglobin gene sequences to activate specific genes in erythroidcells. To test these models, we generated transgenic mice whichcontain the human ^A $gamma$ -globin gene linked to a 576-bp fragment containing the human $beta$ -spectrin promoter. In these mice, the $beta$ -spectrin ^A $gamma$ -globin ( $beta$ sp/^A $gamma$ ) transgene was expressed at high levels in erythroid cells throughoutdevelopment. Transgenic mice containing a 40-kb cosmid constructwith the micro-LCR, $beta$ sp/^A $gamma$ -, $psi$ $beta$ -, $delta$ -, and $beta$ -globin genes showed no developmental switchingand expressed both human $gamma$ - and $beta$ -globin mRNAs in erythroid cellsthroughout development. Mice containing control cosmids with the^A $gamma$ -globin gene promoter showed developmental switching and expressed^A $gamma$ -globin mRNA in yolk sac and fetal liver erythroid cells and $beta$ -globin mRNA in fetal liver and adult erythroid cells. Our resultssuggest that replacement of the $gamma$ -globin promoter with the $beta$ -spectrinpromoter allows the expression of the $beta$ -globin gene. We concludethat the $gamma$ -globin promoter is necessary and sufficient to suppressthe expression of the $beta$ -globin gene in yolk sac erythroid cells.

^* Corresponding author. Mailing address: Hematopoiesis Section, Genetics and Molecular Biology Branch, National Human GenomeResearch 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.

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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Substitution of the Human -Spectrin Promoter for the Human A-Globin Promoter Prevents Silencing of a Linked Human -Globin Gene in Transgenic Mice

Substitution of the Human $beta$ -Spectrin Promoter for the Human ^A $gamma$ -Globin Promoter Prevents Silencing of a Linked Human $beta$ -Globin Gene in Transgenic Mice