Somatic gene therapy of hemoglobinopathies depends initially on the demonstration of safe, efficient gene transfer and long-term, high-level expression of the transferred human beta-globin gene in animal models. We have used a beta-globin gene/beta-locus control region retroviral vector containing several modifications to optimize gene transfer and expression in a mouse transplant model. In thi...

Phylogenetic inferences drawn from comparative data on mammalian -globin gene clusters indicate that the ancestral primate cluster contained a locus control region (LCR) and five paralogously related -type globin loci (5 -LCR-3 ), with and expressed solely during embryonic life. A locus tandem duplication (5 12-3 ) triggered ’s evolution toward fetal expression but by a different trajectory in ...

Alpha thalassemia is a genetic disease characterized by insufficient expression or definite absence of the α-globin chain. Three large deletions (thal-1; 26.5 kb MedII, 20.5 and 17.4 MedI) two small (thal-2; 4.2 3.7 kb) have been in our country. In addition, different PolyA mutations (PA1: AATAAA>AATAAG PA2: AATAAA>AATGA) on α2-globin gene (αα/αPAα), 5nt deletion (αα/α5ntα), unstable Hb v...

The sensitivity to digestion by DNase I of chromatin containing the alpha- and beta(major)-globin genes and the pattern of DNA methylation near these genes was examined during hexamethylenebisacetamide (HMBA)-mediated erythroid differentiation of murine erythroleukemia cells (MELC). In uninduced and induced cells, the chromatin regions containing the alpha- and beta-(major)-globin genes are mor...

The inverse relationship between expression and methylation of -type globin genes is well established. However, little is known about the relationship between expression and methylation of avian -type globin genes. The embryonic globin promoter was unmethylated, and -globin RNA was easily detected in 5-day chicken erythroid cells. A progressive methylation of the CpG dinucleotides in the promot...

Hemoglobinopathies such as sickle cell anemia and b-thalassemia result from among the most common single gene defects worldwide. A promising approach for the treatment of these conditions is through the induction of increased fetal hemoglobin (HbF) expression. Hydroxyurea, which is currently part of the standard treatment of sickle cell anemia, causes increased expression of HbF. However, the l...

After screening a bacterial artificial chromosome of human genomic DNA library with human HS-40, zeta-, alpha-, and theta-globin probes, a 110-kb clone bearing the whole human alpha-globin gene cluster was obtained and rare restriction endonuclease mapping was performed. The bacterial artificial chromosome DNA was isolated, and transgenic mice were generated. Three founders were detected from 3...

Alpha-thalassemia is the most common inherited disorder of hemoglobin synthesis. Genomic deletions involving the alpha-globin gene cluster on chromosome 16p13.3 are the most frequent molecular causes of the disease. Although common deletions can be detected by a single multiplex gap-PCR, the rare and novel deletions depend on more laborious techniques for their identification. The multiplex lig...

BACKGROUND Human globin gene expression is precisely regulated by a complicated network of transcription factors and chromatin modifying activities during development and erythropoiesis. Eos (Ikaros family zinc finger 4, IKZF4), a member of the zinc finger transcription factor Ikaros family, plays a pivotal role as a repressor of gene expression. The aim of this study was to examine the role of...

We have mapped the DNase I-hypersensitive sites around the epsilon-globin and c-myc genes in two human leukemia cell lines K562 and HL60. In K562 cells in which the epsilon-globin gene is transcribed, six DNase I-hypersensitive sites are found in 6 kilobases (kb) of upstream flanking DNA; in HL60 cells in which the c-myc gene is expressed, two DNase I-hypersensitive sites are observed in 2 kb o...