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The molecular mechanisms responsible for the human fetal-to-adult hemoglobin switch have not yet been elucidated. Point mutations identified in the promoter regions of gamma-globin genes from individuals with nondeletion hereditary persistence of fetal hemoglobin (HPFH) may mark cis-acting sequences important for this switch, and the trans-acting factors which interact with these sequences may be integral parts in the puzzle of gamma-globin gene regulation. We have used gel retardation and footprinting strategies to define nuclear proteins which bind to the normal gamma-globin promoter and to determine the effect of HPFH mutations on the binding of a subset of these proteins. We have identified five proteins in human erythroleukemia cells (K562 and HEL) which bind to the proximal promoter region of the normal gamma-globin gene. One factor, gamma CAAT, binds the duplicated CCAAT box sequences; the -117 HPFH mutation increases the affinity of interaction between gamma CAAT and its cognate site. Two proteins, gamma CAC1 and gamma CAC2, bind the CACCC sequence. These proteins require divalent cations for binding. The -175 HPFH mutation interferes with the binding of a fourth protein, gamma OBP, which binds an octamer sequence (ATGCAAAT) in the normal gamma-globin promoter. The HPFH phenotype of the -175 mutation indicates that the octamer-binding protein may play a negative regulatory role in this setting. A fifth protein, EF gamma a, binds to sequences which overlap the octamer-binding site. The erythroid-specific distribution of EF gamma a and its close approximation to an apparent repressor-binding site suggest that it may be important in gamma-globin regulation.  相似文献   

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To test the role of CACCC box on gamma-globin gene activation, the CACCC box was deleted or mutated and gamma-gene expression was monitored in transgenic mice. Disruption of the CACCC box had no effect on gamma-gene expression in the cells of embryonic erythropoiesis but it strikingly reduced gamma-gene expression in fetal erythropoiesis, and abolished gamma-gene expression in adult erythroid cells. The CACCC mutation diminished HS formation, as well as TBP and polII recruitment at the gamma-gene promoter; however, it only resulted in slight or no effects on histone H3 and H4 acetylation in adult erythropoiesis. Our findings indicate that each basic cis element of the proximal gamma-gene promoter, i.e. CACCC, CCAAT or TATA box, can be disrupted without affecting the activation of gamma gene in embryonic erythroid cells. We propose that the trans factors recruited by the three boxes interact with each other to form a 'promoter complex'. In embryonic erythropoiesis the locus control region enhancer is able to interact with the complex even when components normally binding to one of the motifs are missing, but it can only activate an intact 'promoter complex' in adult erythroid cells.  相似文献   

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The X box in the DRA promoter of the human histocompatibility complex is required for expression of the DRA gene in B cells. We show that a B-cell factor binds to a sequence that is clearly distinguishable from binding sites for the previously described X box binding nuclear proteins RF-X, NF-X, NF-Xc, NF-S, hXBP, and AP-1. Mutations in the DRA X box that disrupt the binding of this factor result in a lower level of gene expression, as does the presence of Id (a trans-dominant regulatory protein that negatively regulates helix-loop-helix proteins). Furthermore, this factor is recognized by antibodies directed against the helix-loop-helix protein A1, a mouse homolog of the immunoglobulin enhancer binding proteins E12/E47, and it binds to sequences in other genes that were previously shown to bind these proteins. By these criteria, this factor is BCF-1.  相似文献   

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KLFs对珠蛋白基因表达和红系分化的调控作用   总被引:2,自引:0,他引:2  
Krüppel样因子(Krüppel-like factors, KLFs)是一组与真核基因转录调控密切相关的锌指蛋白.KLFs高度保守的羧基末端含3个串联的Cys2His2型锌指结构,用于结合GC盒和CACCC盒等DNA序列. 红细胞中特异表达的珠蛋白基因和许多红系调控因子中都含有CACCC盒.已有研究发现,多个KLFs通过结合CACCC盒参与调控珠蛋白基因表达和红系分化,例如,KLF1通过结合β-珠蛋白启动子和位点控制区(locus control region, LCR),促进β-珠蛋白的表达、γ-向β-珠蛋白基因的转换和红系分化;KLF2、KLF11和KLF13分别促进ε-和γ-珠蛋白基因的表达;KLF4促进α-和γ-珠蛋白基因的表达;KLF3和KLF8则抑制ε-和γ-珠蛋白基因的表达. 本文综述了KLFs调控珠蛋白基因表达和红系分化的研究进展.  相似文献   

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Transgenic mice carrying an (A)gamma gene construct containing a -382 5' truncation of the (A)gamma gene promoter have a phenotype of hereditary persistence of fetal hemoglobin (HPFH) but, when the CACCC box of the -382(A)gamma promoter is deleted, there is no gamma gene expression in the adult mice. We used this system to investigate the mechanism whereby human HPFH mutations result in gamma gene expression in the adult. Introduction of the -198 T-->C HPFH mutation into the CACCC-less (A)gamma gene construct re-established the HPFH phenotype, indicating that this mutation increases promoter strength, most probably by establishing a novel CACCC box sequence in the -198(A)gamma region. The HPFH phenotype was also re-established when the -117 C-->T HPFH mutation was introduced into a -141(A)gamma promoter with a destroyed CACCC box, indicating that this mutation increases gamma promoter strength in the absence of the CACCC motif. The T-->A -175 HPFH mutation failed to re-establish the HPFH phenotype when the CACCC box was deleted, indicating that gamma gene expression in this mutation is CACCC box dependent. These results provide the first in vivo experimental evidence in support of mechanistic heterogeneity of the non-deletion HPFH mutants.  相似文献   

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The competition model of globin gene regulation states that the gamma-globin gene precludes expression of the beta-globin gene in early development by competing for the enhancing activity of the locus control region. The gamma-globin gene with a -161 promoter is sufficient for suppressing beta-globin gene expression, and the gamma-globin TATA and CACCC elements are necessary for this effect. In this work, stable transfection and transgenic mouse assays have been performed with constructs containing HS3 and HS2 from the locus control region, the gamma-globin gene with promoter mutation(s), and the beta-globin gene. The data indicate that the gamma-globin TATA and CACCC elements together have at least an additive effect on the beta/gamma-globin mRNA ratio in early erythroid cells, suggesting that the elements work coordinately to suppress beta-globin gene expression. The TATA and CACCC are the major gamma-globin promoter elements responsible for this effect. Transgenic mouse experiments indicate that the gamma-globin TATA element plays a role in gamma-globin expression and beta-globin suppression in the embryo and fetus; in contrast, the CACCC element has a stage-specific effect in the fetus. The results suggest that, as is true for the erythroid Krüppel-like factor (EKLF) and the beta-globin promoter CACCC, a protein(s) binds to the gamma-globin CACCC element to coordinate stage-specific gene expression.  相似文献   

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