The role of EKLF in human β-globin gene competition

We have investigated the role of erythroid Kruppel-like factor (EKLF) in expression of the human β-globin genes in compound EKLF knockout/human β- locus transgenic mice. EKLF affects only the adult mouse β-globin genes in homozygous knockout mice; heterozygous mice are unaffected. Here we show that EKLF knockout mice express the human ε and γ-globin genes normally in embryonic red cells. However, fetal liver erythropoiesis, which is marked by a period of γ- and β-gene competition in which the genes are alternately transcribed, exhibits an altered ratio of γ- to β-gene transcription. EKLF heterozygous fetal livers display a decrease in the number of transcriptionally active β genes with a reciprocal increase in the number of transcriptionally active γ genes. β-gene transcription is absent in homozygous knockout fetuses with coincident changes in chromatin structure at the β promoter. There is a further increase in the number of transcriptionally active γ genes and accompanying γ gene promoter chromatin alterations. These results indicate that EKLF plays a major role in γ- and β-gene competition and suggest that EKLF is important in stabilizing the interaction between the Locus Control Region and the β-globin gene. In addition, these findings provide further evidence that developmental modulation of globin gene expression within individual cells is accomplished by altering the frequency and/or duration of transcriptional periods of a gene rather than changing the rate of transcription.