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Genome Architecture of the Human ß-Globin Locus Affects Developmental Regulation of Gene Expression

Department of Biochemistry and Molecular Biology,¹ Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas 66160,³ Division of Medical Genetics, University of Washington, Seattle, Washington 98195²

Received 16 January 2005/ Returned for modification 10 February 2005/ Accepted 21 July 2005

To test the role of gene order in globin gene expression, mutant human ß-globin locus yeast artificial chromosome constructs were used, each having one additional globin gene encoding a "marked" transcript (^m, ^m, or ß^m) integrated at different locations within the locus. When a ß^m-globin gene was placed between the locus control region (LCR) and the -globin gene, ß^m-globin expression dominated primitive and definitive erythropoiesis; only ß^m-globin mRNA was detected during the fetal and adult definitive stages of erythropoiesis. When an ^Am-globin gene was placed at the same location, ^Am-globin was expressed during embryonic erythropoiesis and the fetal liver stage of definitive erythropoiesis but was silenced during the adult stage. The downstream wild-type -globin genes were not expressed. When an ^m-globin gene was placed between the - and ß-globin genes, it remained silent during embryonic erythropoiesis; only the LCR-proximal wild-type -globin gene was expressed. Placement of a ß^m-globin gene upstream of the ^G-globin gene resulted in expression of ß^m-globin in embryonic cells and in a significant decrease in expression of the downstream wild-type ß-globin gene. These results indicate that distance from the LCR, an inherent property of spatial gene order, is a major determinant of temporal gene expression during development.

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