The Human γ-Globin TATA and CACCC Elements Have Key, Distinct Roles in Suppressing β-Globin Gene Expression in Embryonic/Fetal Development

The competition model of globin gene regulation states that the γ-globin gene precludes expression of the β-globin gene in early development by competing for the enhancing activity of the locus control region. The γ-globin gene with a −161 promoter is sufficient for suppressing β-globin gene expression, and the γ-globin TATA and CACCC elements are necessary for this effect. In this work, stable transfection and transgenic mouse assays have been performed with constructs containing HS3 and HS2 from the locus control region, the γ-globin gene with promoter mutation(s), and the β-globin gene. The data indicate that the γ-globin TATA and CACCC elements together have at least an additive effect on the β/γ-globin mRNA ratio in early erythroid cells, suggesting that the elements work coordinately to suppress β-globin gene expression. The TATA and CACCC are the major γ-globin promoter elements responsible for this effect. Transgenic mouse experiments indicate that the γ-globin TATA element plays a role in γ-globin expression and β-globin suppression in the embryo and fetus; in contrast, the CACCC element has a stage-specific effect in the fetus. The results suggest that, as is true for the erythroid Krüppel-like factor (EKLF) and the β-globin promoter CACCC, a protein(s) binds to the γ-globin CACCC element to coordinate stage-specific gene expression.