Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 25, Issue 20, Pages 8765-8778Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.25.20.8765-8778.2005
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Funding
- NHLBI NIH HHS [R56 HL067336, HL67336, R01 HL067336] Funding Source: Medline
- NIDDK NIH HHS [R01 DK061804, DK53510, DK61804] Funding Source: Medline
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To test the role of gene order in globin gene expression, mutant human P-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 E-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 e-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.
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