Genome architecture of the human beta-globin locus affects developmental regulation of gene expression.
To test the role of gene order in globin gene expression, mutant human beta-globin locus yeast artificial chromosome constructs were used, each having one additional globin gene encoding a "marked" transcript (epsilon(m), gamma(m), or beta(m)) integrated at different locations within the locus. When a beta(m)-globin gene was placed between the locus control region (LCR) and the epsilon-globin gene, beta(m)-globin expression dominated primitive and definitive erythropoiesis; only beta(m)-globin mRNA was detected during the fetal and adult definitive stages of erythropoiesis. When an (A)gamma(m)-globin gene was placed at the same location, (A)gamma(m)-globin was expressed during embryonic erythropoiesis and the fetal liver stage of definitive erythropoiesis but was silenced during the adult stage. The downstream wild-type gamma-globin genes were not expressed. When an epsilon(m)-globin gene was placed between the delta- and beta-globin genes, it remained silent during embryonic erythropoiesis; only the LCR-proximal wild-type epsilon-globin gene was expressed. Placement of a beta(m)-globin gene upstream of the (G)gamma-globin gene resulted in expression of beta(m)-globin in embryonic cells and in a significant decrease in expression of the downstream wild-type beta-globin gene. These results indicate that distance from the LCR, an inherent property of spatial gene order, is a major determinant of temporal gene expression during development.
Harju
Susanna
S
Department of Biochemistry and Molecular Biology, MS 3030, University of Kansas Medical Center, Kansas City, 66160-7421, USA.
Navas
Patrick A
PA
Stamatoyannopoulos
George
G
Peterson
Kenneth R
KR
D000818:Animals; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D004920:Erythropoiesis / Q000235:genetics; D005260:Female; D005333:Fetus / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D023061:Gene Order; D020868:Gene Silencing; D015894:Genome, Human; D005914:Globins / Q000235:genetics*; D006801:Humans; D019901:Locus Control Region; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D011247:Pregnancy
D005914:Globins