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• W2551276222 abstract "Abstract AHSP is an erythroid-specific protein that complexes with free α-hemoglobin, protecting it from precipitation. AHSP has been proposed as a modifier gene in β thalassemia and as a candidate gene for unexplained Heinz body anemias, thus understanding its regulation may lead to novel therapies for these disorders. Identified as an erythroid-specific, GATA-1 inducible gene, decreased AHSP mRNA has been found in the fetal livers of mice deficient in the erythroid transcription factor EKLF by both microarray and RNA subtraction analysis. In fetal livers from d13.5 EKLF-deficient mice, AHSP/α-globin mRNA ratios were decreased to 11–16% of wild type by RT-PCR and RPA. In the same fetal livers, no AHSP protein was detected on Western blots with a MoAB against AHSP. EKLF interacts with the proximal CACCC box of the β-globin gene promoter, establishing local chromatin structure and directing high-level β-globin transcription. We hypothesized that chromatin across the AHSP locus would be perturbed in erythroid cells from EKLF-deficient mice. We performed DNase I hypersensitive site (HS) mapping and chromatin immunoprecipitation (ChIP) analysis using wild type and EKLF deficient fetal liver cells. A strong HS was identified in the AHSP 5′ flanking DNA in the core promoter region, that was absent in day 13.5 fetal liver DNA from EKLF-deficient mice. Fine mapping placed this 5′ HS over a CACCC site in the core AHSP promoter. ChIP across the entire AHSP locus with d13.5 fetal liver chromatin identified 2 regions of hyperacetylation of histones H3 and H4 in wild type mice, one corresponding to the 5′ HS and the other 3′ to the AHSP coding sequence. Both of these hyperacetylated regions were hypoacetylated in EKLF-deficient fetal liver cells. ChIP across the AHSP locus with chromatin obtained from mice with an HA tag knocked into the 3′ end of the EKLF gene identified a peak of EKLF binding extending from the 5′HS to intron one, peaking over the core promoter CACCC site. The sequence of this region (ACCCACCCT) has a single mismatch compared to the EKLF consensus site (CCNCNCCCN). Using the AHSP CACCC site as probe in mobility shift assays with rEKLF protein yielded a complex that migrated at the same mobility as a complex obtained with a control β-globin promoter CACCC site probe. Both AHSP and control β-globin complexes were effectively competed by an excess of unlabeled AHSP probe, unlabeled β-globin probe, or ELKF antiserum. Mutant AHSP CACCC probes did not form DNA-protein complexes nor did they effectively displace wild type AHSP CACCC or β-globin CACCC probes in competition assays. Probes with the AHSP CACCC site mutated to the β-globin sequence (A to C) or the other 2 possibilities (A to G, A to T) yielded complexes comparable to wild type AHSP and control β-globin CACCC probes. In transfection assays in K562 cells, an AHSP promoter-luciferase reporter plasmid was transactivated by an EKLF expression plasmid to a degree comparable to a β-globin promoter-luciferase plasmid. These results support the hypotheses that the hemolytic anemia in EKLF-deficient mice is exacerbated by decreased AHSP expression and that EKLF acts as a transcription factor and a chromatin modulator for genes other than β-globin. Our data also support the hypothesis that AHSP and EKLF may be modifier genes for the β-thalassemia syndromes." @default.
• W2551276222 created "2016-11-30" @default.
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• W2551276222 date "2005-11-16" @default.
• W2551276222 modified "2023-09-28" @default.
• W2551276222 title "The Human Alpha Hemoglobin Stabilizing Protein (AHSP) Gene Locus in EKLF-Deficient Erythroid Cells." @default.
• W2551276222 doi "https://doi.org/10.1182/blood.v106.11.1740.1740" @default.
• W2551276222 hasPublicationYear "2005" @default.
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