Analysis of the Human α-Globin Gene Cluster in Transgenic Mice

A 350-bp segment of DNA associated with an erythroid-specific DNase I-hypersensitive site (HS -40), upstream of the α-globin gene cluster, has been identified as the major tissue-specific regulator of the α-globin genes. However, this element does not direct copy number-dependent or developmentally stable expression of the human genes in transgenic mice. To determine whether additional upstream hypersensitive sites could provide more complete regulation of α gene expression we have studied 17 lines of transgenic mice bearing various DNA fragments containing HSs -33, -10, -8, and -4, in addition to HS -40. Position-independent, high-level expression of the human ζ- and α-globin genes was consistently observed in embryonic erythroid cells. However, the additional HSs did not confer copy-number dependence, alter the level of expression, or prevent the variable down-regulation of expression in adults. These results suggest that the region upstream of the human α-globin genes is not equivalent to that upstream of the β locus and that although the two clusters are coordinately expressed, there may be differences in their regulation.