title: Linear distance from the locus control region determines epsilon-globin transcriptional activity.
abstract: 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 beta-globin locus control region (LCR) activates expression of five genes in erythroid cells, including the proximal embryonic epsilon- and the distal adult beta-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, epsilon-globin gene expression decreased by 90%, while the more distantly located gamma- or beta-globin genes were not affected. Remarkably, introduction of a consensus EKLF binding site into the epsilon-globin promoter rendered its expression distance insensitive; when tested in an EKLF-null genetic background, expression of the mutant epsilon-globin gene was severely compromised. Thus, the epsilon-globin gene differs in its distance sensitivity to the LCR from the other beta-like globin genes, which is, at least in part, determined by the transcription factor EKLF.
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Motoshi
authors.initials: M
authors.lastname: Shimotsuma
authors.forename: Hitomi
authors.initials: H
authors.lastname: Matsuzaki
authors.forename: Osamu
authors.initials: O
authors.lastname: Tanabe
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Campbell
authors.forename: James Douglas
authors.initials: JD
authors.lastname: Engel
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanimoto
mesh_terms: D000818:Animals; D010582:Bacteriophage lambda / Q000235:genetics; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D005914:Globins / Q000235:genetics*; D006801:Humans; D020014:K562 Cells; D019901:Locus Control Region / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D014158:Transcription, Genetic / Q000235:genetics*; D014162:Transfection
chemical_list: D005914:Globins