Binary transgenic mouse model for studying the trans control of globin gene switching: Evidence that GATA-1 is an in vivo repressor of human ɛ gene expression

To test whether human GATA-1 (hGATA-1) is involved in the transcriptional control of globin gene switching, we produced transgenic mice overexpressing hGATA-1, crossed them with mice carrying a human β-globin locus yeast artificial chromosome (βYAC), and analyzed globin gene expression in their progeny. Mice carrying both the hGATA-1 and the βYAC transgenes had normal levels of γ- and β-globin mRNA and no distortion in the rate or in the timing of γ-to-β switch, indicating that hGATA-1 is not involved in the developmental control of γ- and β-globin genes. In contrast, mice carrying the hGATA-1 and the βYAC transgenes had 5- to 6-fold lower expression of the human ɛ globin gene compared with βYAC mice lacking the hGATA-1 transgene. These results provide direct in vivo evidence that hGATA-1 is a specific repressor of human ɛ gene expression. Our findings also suggest that binary transgenic mouse systems based on overexpression of transcriptional factors can be used to investigate the trans control of human globin gene switching. Systems as the one we describe here should be useful in the study of any developmentally controlled human gene for which transgenic mice are available.