The study of sequence configuration and functional impact of the (AC)n(AT)xTy motif in human β‐globin gene promoter

Chan, Ply; S.K., Edmond; Philipsen, Sjaak; Tan-Un, KC

doi:10.1002/ajh.20836

Cited by 5 publications

(3 citation statements)

References 19 publications

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“…(17, 23) This particular AT repeat motif was associated with the lowest HBB mRNA expression in differentiated MEL cells. (24) A similar AT motif was associated with β thalassemia in carriers without a detectable mutation in HBB. (25, 26) HBB suppression might play a role in the high level of γ-globin gene expression found with the AI haplotype.…”

Section: Discussionmentioning

confidence: 97%

Fetal hemoglobin in sickle cell anemia: Genetic studies of the Arab-Indian haplotype

Ngo

Bae

Steinberg

et al. 2013

Blood Cells, Molecules, and Diseases

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Sickle cell anemia is common in the Middle East and India where the HbS gene is sometimes associated with the Arab-Indian (AI) β-globin gene (HBB) cluster haplotype. In this haplotype of sickle cell anemia, fetal hemoglobin (HbF) levels are 3-4 fold higher than those found in patients with HbS haplotypes of African origin. Little is known about the genetic elements that modulate HbF in AI haplotype patients. We therefor studied Saudi HbS homozygotes with the AI haplotype (mean HbF 19.2±7.0%, range 3.6 to 39.6%) and known genotyped cis- and trans-acting elements associated with HbF expression. All cases, regardless of HbF concentration, were homozygous for AI haplotype-specific elements cis to HBB. SNPs in BCL11A and HBS1L-MYB that were associated with HbF in other populations explained only 8.8% of the variation of HbF. KLF1 polymorphisms associated previously with high HbF were not present In the 44 patients tested. The SNPs and genetic loci we have chosen for this study do not explain the high HbF in sickle cell patients with AI haplotype or its variation among patients with this haplotype. The dispersion of HbF levels among AI haplotype patients suggests that other genetic elements modulate the effects of the known cis- and trans-acting regulators. These regulatory elements, which remain to be discovered, might be specific in the Saudi and some other populations where HbF levels are especially high.

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Section: Discussionmentioning

confidence: 97%

Fetal hemoglobin in sickle cell anemia: Genetic studies of the Arab-Indian haplotype

Ngo

Bae

Steinberg

et al. 2013

Blood Cells, Molecules, and Diseases

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“…An interesting study by Chan et al (2007) showed association between the (AC) 3 (AT) 7 (T) 5 configuration and raised HbF levels among the Chinese population 24. They suggested that (AC) n (AT) x (T) y configuration may have an association with the HPFH phenotype which acts by suppression of the β globin gene expression.…”

Section: Discussionmentioning

confidence: 99%

Effect of Cis Acting Potential Regulators in the Ss Globin Gene Cluster on the Production of HBF in Thalassemia Patients

Nadkarni

2013

Mediterr J Hematol Infect Dis

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The clinical presentation of β-thalassemia intermedia phenotypes are influenced by many factors. The persistence of fetal hemoglobin and several polymorphisms located in the promoters of γ- and β-globin genes are some of them. The aim of this study was to evaluate the combined effect of the −158 Gγ (C→T) polymorphism and of the (AT)x(T)y configuration, as well as their eventual association with elevated levels of HbF in β-thalassemia carriers, β-thalassemia intermedia, β-thalassemia major and normal controls of Indian origin. The −158 Gγ T allele was found to be associated with increased levels of HbF in β thalassemia carriers, and not in wild-type subjects. In the homozygous group, the −158 Gγ T allele was significantly higher in the thalassemia intermedia group (66%) as against the thalassemia major group (21%). The (AT)9(T)5 allele did not show any association with raised HbF levels. However 24% of milder cases showed presence of this allele. This study suggests that two regions of the β globin cluster, whether in cis or in trans to each other, can interact to enhance HbF expression when a β thalassemic determinant is present in heterozygosity and help in amelioration of the severity of the disease in homozygotes.

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“…To search for genetic determinants of different levels of HBG gene expression we first carried out an extensive sequence analysis of putative regulatory regions within the HBB cluster that were potentially involved in these mechanisms. We examined sequence variations in binding sites for transcriptional factors or in polymorphic sequences within the hypersensitive site‐2 (HS‐2) of the locus control region (LCR) (Öner et al , 1992) and the promoter region of the HBG2 and HBB genes (Berg et al , 1991; Pissard & Beuzard, 1994; Chang et al , 1995; Lu & Steinberg, 1996; Chan et al , 2007), all of which had been reported to be involved in modulation of globin gene expression (Table II). The same HBB cluster genotype was found in the three patients and we were able to exclude known HPFH mutations and hypothetical parental germ line rearrangements within this locus.…”

Section: Resultsmentioning

confidence: 99%

research paper: Role of the cold shock domain protein A in the transcriptional regulation of HBG expression

Petruzzelli¹,

Gaudino²,

Amendola³

et al. 2010

Br J Haematol

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Summary Impaired switching from fetal haemoglobin (HbF) to adult globin gene expression leads to hereditary persistence of fetal haemoglobin (HPFH) in adult life. This is of prime interest because elevated HbF levels ameliorate β‐thalassaemia and sickle cell anaemia. Fetal haemoglobin levels are regulated by complex mechanisms involving factors linked or not to the β‐globin gene (HBB) locus. To search for factors putatively involved in the expression of the γ‐globin genes (HBG1, HBG2), we examined the reticulocyte transcriptome of three siblings who had different HbF levels and different degrees of β‐thalassaemia severity although they had the same ΗBA‐ and ΗΒB cluster genotypes. By mRNA differential display we isolated the cDNA coding for the cold shock domain protein A (CSDA), also known as dbpA, previously reported to interact in vitro with the HBG2 promoter. Expression studies performed in K562 and in primary erythroid cells showed an inverse relationship between HBG and CSDA expression levels. Functional studies performed by Chromatin Immunoprecipitation and reporter gene assays in K562 cells demonstrated that CSDA is able to bind the HBG2 promoter and suppress its expression. Therefore, our study demonstrated that CSDA is a trans‐acting repressor factor of HBG expression and modulates the HPFH phenotype.

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The study of sequence configuration and functional impact of the (AC)_n(AT)_xT_y motif in human β‐globin gene promoter

Cited by 5 publications

References 19 publications

Fetal hemoglobin in sickle cell anemia: Genetic studies of the Arab-Indian haplotype

Fetal hemoglobin in sickle cell anemia: Genetic studies of the Arab-Indian haplotype

Effect of Cis Acting Potential Regulators in the Ss Globin Gene Cluster on the Production of HBF in Thalassemia Patients

research paper: Role of the cold shock domain protein A in the transcriptional regulation of HBG expression

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