Linear distance from the locus control region determines ε-globin transcriptional activity

Enhancer elements modulate promoter activity over vast chromosomal distances, and mechanisms that ensure restrictive interactions between promoters and enhancers are critical for proper control of gene expression. The human β-globin locus control region (LCR) activates expression of five genes in erythroid cells, including the proximal embryonic ε- and the distal adult β-globin genes. To test for possible distance sensitivity of the genes to the LCR, we extended the distance between the LCR and genes by 2.3 kbp within the context of a yeast artificial chromosome, followed by the generation of transgenic mice (TgM). In these TgM lines, ε-globin gene expression decreased by 90%, while the more distantly located γ- or β-globin genes were not affected. Remarkably, introduction of a consensus EKLF binding site into the e-globin promoter rendered its expression distance insensitive; when tested in an EKLF-null genetic background, expression of the mutant e-globin gene was severely compromised. Thus, the ε-globin gene differs in its distance sensitivity to the LCR from the other β-like globin genes, which is, at least in part, determined by the transcription factor EKLF.