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Human Molecular Genetics, 2002, Vol. 11, No. 8 893-903
© 2002 Oxford University Press

Activation of the ß-like globin genes in transgenic mice is dependent on the presence of the ß-locus control region

Patrick A. Navas, Qiliang Li, Kenneth R. Peterson1, Richard A. Swank2, Alex Rohde, Julianne Roy and George Stamatoyannopoulos*

1Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA 2Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA 3Organon Pharmaceuticals Inc., Seattle Region, W. Orange, NJ 07052, USA

The ß-globin locus control region (LCR) is a powerful regulatory element required for high-level globin gene expression. We have generated transgenic mouse lines carrying a ß-globin locus yeast artificial chromosome lacking the LCR to determine if the LCR is required for globin gene activation. ß-Globin gene expression was analyzed by RNase protection, but no detectable levels of {varepsilon}-, {gamma}- and ß-globin gene transcripts were produced at any stage of development. These findings suggest that the presence of the LCR is a minimum requirement for globin gene expression. Next, we tested whether the LCR is necessary to activate globin gene expression in a {gamma}-globin promoter mutant that causes hereditary persistence of fetal hemoglobin (HPFH). ß-YAC transgenic mice carrying the -117 HPFH mutation and a HS3 core deletion that specifically abolishes {gamma}-globin gene expression during definitive erythropoiesis were produced to test whether the -117 A{gamma} promoter is activated in the absence of interaction with the LCR. In four transgenic mouse lines, {gamma}-globin gene expression was absent in adult erythrocytes, suggesting that an interaction between the {gamma}-globin gene promoter and the LCR is required for {gamma} gene activation even when the promoter contains an HPFH mutation.

* To whom correspondence should be addressed at: Tel: +1 206 543 3526; Fax: +1 206 543 3050; Email: gstam@u.washington.edu


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