Fetal hemoglobin expression in the compound heterozygous state for ?117 (G?A)A? HPFH and IVSII-745 (C?G) ?+ thalassemia: A case study

Dedoussis, George; Sinopoulou, Klio; Gyparaki, Marilena; Loutradis, Aphroditi

doi:10.1002/(sici)1096-8652(199906)61:2<139::aid-ajh12>3.0.co;2-7

Cited by 13 publications

(6 citation statements)

References 37 publications

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“…Patients bearing H ereditary P ersistence of F etal H emoglobin (HPFH) mutations have high levels of fetal γ-hemoglobin (HbF) that aberrantly persist into adulthood [3]. It has been observed clinically that the co-inheritance of an HPFH mutation in SCD patients significantly mitigates SCD symptoms [4]–[7]. Thus, for the past three decades, the scientific community has made concerted efforts to develop strategies by which we might safely and efficiently induce HbF synthesis in adult definitive erythroid cells as a potential therapy to treat SCD.…”

Section: Introductionmentioning

confidence: 99%

Biased, Non-equivalent Gene-Proximal and -Distal Binding Motifs of Orphan Nuclear Receptor TR4 in Primary Human Erythroid Cells

et al. 2014

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We previously reported that TR2 and TR4 orphan nuclear receptors bind to direct repeat (DR) elements in the ε- and γ-globin promoters, and act as molecular anchors for the recruitment of epigenetic corepressors of the multifaceted DRED complex, thereby leading to ε- and γ-globin transcriptional repression during definitive erythropoiesis. Other than the ε- and γ-globin and the GATA1 genes, TR4-regulated target genes in human erythroid cells remain unknown. Here, we identified TR4 binding sites genome-wide using chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq) as human primary CD34+ hematopoietic progenitors differentiated progressively to late erythroid precursors. We also performed whole transcriptome analyses by RNA-seq to identify TR4 downstream targets after lentiviral-mediated TR4 shRNA knockdown in erythroid cells. Analyses from combined ChIP-seq and RNA-seq datasets indicate that DR1 motifs are more prevalent in the proximal promoters of TR4 direct target genes, which are involved in basic biological functions (e.g., mRNA processing, ribosomal assembly, RNA splicing and primary metabolic processes). In contrast, other non-DR1 repeat motifs (DR4, ER6 and IR1) are more prevalent at gene-distal TR4 binding sites. Of these, approximately 50% are also marked with epigenetic chromatin signatures (such as P300, H3K27ac, H3K4me1 and H3K27me3) associated with enhancer function. Thus, we hypothesize that TR4 regulates gene transcription via gene-proximal DR1 sites as TR4/TR2 heterodimers, while it can associate with novel nuclear receptor partners (such as RXR) to bind to distant non-DR1 consensus sites. In summary, this study reveals that the TR4 regulatory network is far more complex than previously appreciated and that TR4 regulates basic, essential biological processes during the terminal differentiation of human erythroid cells.

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Section: Introductionmentioning

confidence: 99%

Biased, Non-equivalent Gene-Proximal and -Distal Binding Motifs of Orphan Nuclear Receptor TR4 in Primary Human Erythroid Cells

et al. 2014

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“…When haplotype IIIa was associated with the ␤-globin mutation combined with the XmnI site in-cis or in-trans (one case), or in the homozygous state, high HbF levels were measured. We have recently published [30] a case study from a Greek family, where one of the individus had co-inherited in-trans the IVSII-745 (C→G) ␤ + thalassaemia with the G ␥ −158 C→T. This double heterozygote presented HbF levels 3.7%, with a G ␥/ A ␥ ratio 69/31.…”

Section: Discussionmentioning

confidence: 71%

HbF production in β thalassaemia heterozygotes for the IVS-II-1 G→A β0-globin mutation. Implication of the haplotype and theGγ-158 C→T mutation on the HbF level

et al. 2000

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We studied the presence of the XmnI site and the ␤-globin haplotype in 24 individuals, carriers of the IVSII-1 G→A ␤ 0 -globin mutation, of whom fourteen had no detectable levels of HbF, while ten coming from 5 families, presented HbF levels ranging from 1.7 to 9% of the total Hb. Of these ␤-thalassaemia heterozygotes with fetal hemoglobin, 6 were females and 4 were males with median HbF levels of 4.85% and 4% respectively, and an excess of G

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“…Therefore, it seems this particular deletion is linked to the normal b-globin gene in the majority of individuals with normal Hb F levels. However, other studies have reported a reduction of A g-globin gene production in individuals with this 4 bp deletion (29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

Molecular Analysis of γ-Globin Promoters, HS-111 and 3′HS1, in β-thalassemia Intermedia Patients Associated with High Levels of Hb F

et al. 2009

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The nucleotide (nt) variations in the promoter region of the gamma-globin genes, HS-111 and 3'HS1 regions, were studied in Iranian patients with beta-thalassemia intermedia (beta-TI), beta-thalassemia major (beta-TM) and healthy individuals. Of the five nt variations at the 5' end of the (A)gamma-globin gene, -369 (C>G), -611 (-T) and -603/604 (GA>AG) were found in all samples, whereas -588 (A>G) and -AAGC at -222 to -225 were found at different frequencies in the studied groups. Therefore, the -369, -611 and -603/604 variations were considered common mutations in this population, and the difference with respect to the -AAGC deletion was not significant. However, the A allele of the -588 variation and [+] allele of the XmnI polymorphism were more frequent in beta-TI patients, especially those who had the IVS-II-1(G>A)/IVS-II-1(G>A) genotype. The + allele of XmnI also had complete correlation with the A allele of -588 variation. The HS-111 (-21 A) variation also showed association with beta-TI patients who had high levels of Hb F. Bearing in mind that the -588 variation lies within the postulated adult-specific silencer region and that the majority of beta-TI patients had allele A, then it can be envisaged that this allele could have a role in altering the repressor function at this region. Therefore, the A allele of -588, [+] allele of XmnI and HS-111 (-21 A) variation are useful genetic markers to differentiate between beta-TM and beta-TI patients. However, these nt changes alone may not be the only elements raising the level of Hb F, other regulatory and modifying factors also play a role in Hb F production.

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Fetal hemoglobin expression in the compound heterozygous state for ?117 (G?A)A? HPFH and IVSII-745 (C?G) ?+ thalassemia: A case study

Cited by 13 publications

References 37 publications

Biased, Non-equivalent Gene-Proximal and -Distal Binding Motifs of Orphan Nuclear Receptor TR4 in Primary Human Erythroid Cells

Biased, Non-equivalent Gene-Proximal and -Distal Binding Motifs of Orphan Nuclear Receptor TR4 in Primary Human Erythroid Cells

HbF production in β thalassaemia heterozygotes for the IVS-II-1 G→A β0-globin mutation. Implication of the haplotype and theGγ-158 C→T mutation on the HbF level

Molecular Analysis of γ-Globin Promoters, HS-111 and 3′HS1, in β-thalassemia Intermedia Patients Associated with High Levels of Hb F

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