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

Abstract

The β-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 β-globin locus yeast artificial chromosome lacking the LCR to determine if the LCR is required for globin gene activation. β-Globin gene expression was analyzed by RNase protection, but no detectable levels of ε-, γ- and β-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 β-globin promoter mutant that causes hereditary persistence of fetal hemoglobin (HPFH). β-YAC transgenic mice carrying the - 117 HPFH mutation and a HS3 core deletion that specifically abolishes γ-globin gene expression during definitive erythropoiesis were produced to test whether the - 117 Aγ promoter is activated in the absence of interaction with the LCR. In four transgenic mouse lines, γ-globin gene expression was absent in adult erythrocytes, suggesting that an interaction between the γ-globin gene promoter and the LCR is required for γ gene activation even when the promoter contains an HPFH mutation.