In one form of beta-thalassemia, a genetic blood disorder, a mutation in intron 2 of the beta-globin gene (IVS2-654) causes aberrant splicing of beta-globin pre-mRNA and, consequently, beta-globin deficiency. Treatment of mammalian cells stably expressing the IVS2-654 human beta-globin gene with antisense oligonucleotides targeted at the aberrant splice sites restored correct splicing in a dose...

The Krüppel-like factors (KLFs) are a family of C2/H2 zinc finger DNA-binding proteins that are important in controlling developmental programs. Erythroid Krüppel-like factor (EKLF or KLF1) positively regulates the beta-globin gene in definitive erythroid cells. KLF2 (LKLF) is closely related to EKLF and is expressed in erythroid cells. KLF2-/- mice die between embryonic day 12.5 (E12.5) and E1...

Sickle cell disease is a hereditary, autosomal recessive pathology caused by the replacement of adenine thymin in position 6 beta globin gene, producing anomalous hemoglobin (hemoglobin S- HbS). It characterized chronic inflammatory state with hemolytic anemia and vaso-occlusive phenomena occurs when HbS gene homozygosis (SS) or heterozygosis, association other variant hemoglobins (SD, SC, SE) ...

A variant of hereditary persistence of fetal hemoglobin (HPFH), first described in a patient from Seattle, was studied by structural analysis of the gamma-globin genes. A family study suggested that the determinant for this form of HPFH, in which the HbF contains both G gamma- and A gamma-globin chains, segregated with the beta S gene. No deletions or other abnormalities were detected in the fe...

Species differences in the size or membership composition of multigene families can be attributed to lineage-specific additions of new genes via duplication, losses of genes via deletion or inactivation, and the creation of chimeric genes via domain shuffling or gene fusion. In principle, it should be possible to infer the recombinational pathways responsible for each of these different types o...

We have generated a site-specific 17 bp insertion within a 38 kb chick globin gene cluster by employing the recombination abilities of Saccharomyces cerevisiae. This gene cluster contains four beta-type globin genes which share a high degree of sequence homology. In this procedure, a small fragment of beta A-globin DNA containing a 17 bp insertion is subcloned into a URA3-based yeast integratin...

The mechanisms by which pharmacologic agents stimulate gamma-globin gene expression in beta-globin disorders has not been fully established at the molecular level. In studies described here, nucleated erythroblasts were isolated from patients with beta-globin disorders before and with butyrate therapy, and globin biosynthesis, mRNA, and protein-DNA interactions were examined. Expression of gamm...

The human beta-globin locus control region (LCR) confers high-level, tissue-specific expression to the beta-globin genes. Tandem Maf recognition elements (MAREs) within the hypersensitive site 2 (HS2) subregion of the LCR are important for the strong enhancer activity of the LCR. Multiple proteins are capable of interacting with these sites in vitro, including the erythroid cell- and megakaryoc...

Matrix attachment regions (MARs) are important in chromatin organization and gene regulation. Although it is known that there are a number of MAR elements in the beta-globin gene cluster, it is unclear that how these MAR elements are involved in regulating beta-globin genes expression. Here, we report the identification of a new MAR element at the LCR (locus control region) of human beta-globin...