Erythroid Krüppel-Like Factor Is Essential for β-Globin Gene Expression Even in Absence of Gene Competition, But Is Not Sufficient to Induce the Switch From γ-Globin to β-Globin Gene Expression

Abstract

Different genes in the β-like globin locus are expressed at specific times during development. This is controlled, in part, by competition between the genes for activation by the locus control region. In mice, gene inactivation of the erythroid Krüppel-like factor (EKLF) transcription factor results in a lethal anemia due to a specific and substantial decrease in expression of the fetal/adult-stage–specific β-globin gene. In transgenic mice carrying the complete human β-globin locus, EKLF ablation not only impairs human β-globin–gene expression but also results in increased expression of the human γ-globin genes during the fetal/adult stages. Hence, it may appear that EKLF is a determining factor for the developmental switch from γ-globin to β-globin transcription. However, we show here that the function of EKLF for β-globin–gene expression is necessary even in absence of gene competition. Moreover, EKLF is not developmental specific and is present and functional before the switch from γ-globin to β-globin–gene expression occurs. Thus, EKLF is not the primary factor that controls the switch. We suggest that autonomous repression of γ-globin transcription that occurs during late fetal development is likely to be the initiating event that induces the switch.