Effect on gene expression of three allelic variants in GATA motifs of ABO, RHD, and RHCE regulatory elements

Fennell, Katie; Hoffman, Roser; Yoshida, Ken; Iwamoto, Sadahiko; Govender, Lavendri; Vather, Kuben; Sookraj, Ashika; Jentsch, Ute; Pambrun, Chantale; McAuley, Catherine M.; Keller, Margaret; Ochoa‐Garay, Gorka

doi:10.1111/trf.14299

Cited by 9 publications

(13 citation statements)

References 20 publications

(37 reference statements)

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“…1 B) 23 , 24 . As the site includes one transcription factor recognition motif for RUNX1 and two motifs for GATA1/2 25 , 26 , deletion and single-nucleotide substitutions in the RUNX motif in the + 5.8-kb site have been found in individuals with A m , B 3 or B w 26 – 28 , while nucleotide substitutions in the downstream GATA motif of the site have been reported in individuals with B m and A m 25 , 29 , 30 . Thus, erythroid cell-specific regulation of ABO transcription could be dependent upon the + 5.8-kb site and the constitutive ABO promoter 23 , 31 , 32 .…”

Section: Introductionmentioning

confidence: 99%

Emergence of an erythroid cell-specific regulatory region in ABO intron 1 attributable to A- or B-antigen expression on erythrocytes in Hominoidea

Sano

Fukuda

Oishi

et al. 2023

Sci Rep

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A- and B-antigens are present on red blood cells (RBCs) as well as other cells and secretions in Hominoidea including humans and apes such as chimpanzees and gibbons, whereas expression of these antigens on RBCs is subtle in monkeys such as Japanese macaques. Previous studies have indicated that H-antigen expression has not completely developed on RBCs in monkeys. Such antigen expression requires the presence of H-antigen and A- or B-transferase expression in cells of erythroid lineage, although whether or not ABO gene regulation is associated with the difference of A- or B-antigen expression between Hominoidea and monkeys has not been examined. Since it has been suggested that ABO expression on human erythrocytes is dependent upon an erythroid cell-specific regulatory region or the + 5.8-kb site in intron 1, we compared the sequences of ABO intron 1 among non-human primates, and demonstrated the presence of sites orthologous to the + 5.8-kb site in chimpanzees and gibbons, and their absence in Japanese macaques. In addition, luciferase assays revealed that the former orthologues enhanced promoter activity, whereas the corresponding site in the latter did not. These results suggested that the A- or B-antigens on RBCs might be ascribed to emergence of the + 5.8-kb site or the corresponding regions in ABO through genetic evolution.

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Section: Introductionmentioning

confidence: 99%

Emergence of an erythroid cell-specific regulatory region in ABO intron 1 attributable to A- or B-antigen expression on erythrocytes in Hominoidea

Sano

Fukuda

Oishi

et al. 2023

Sci Rep

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“…Promoter variants affect gene expression and regulation. GATA motifs, which are binding sites for the erythroid-specific transcription factor GATA-1, have been shown to play a role in gene expression [13]. In the Duffy blood group system, a mutation in the GATA-1 binding site of the Duffy gene's promoter region results in the Duffy-null phenotype that prevents gene transcription in erythroid cells [14].…”

Section: Introductionmentioning

confidence: 99%

“…Most studies have investigated the exon and intron regions of RHD and RHCE but relatively few studies exist on their promoters. Fennell et al found that variants in the GATA-1 binding site at 5 0 UTR-115C of RHD and 5 0 UTR-83T of RHCE showed a significant reduction in RH gene expression [13]. Denomme et al [15]…”

Section: Introductionmentioning

confidence: 99%

“…Most studies have investigated the exon and intron regions of RHD and RHCE but relatively few studies exist on their promoters. Fennell et al found that variants in the GATA‐1 binding site at 5′ UTR‐115C of RHD and 5′ UTR‐83T of RHCE showed a significant reduction in RH gene expression [13]. Denomme et al [15] investigated the 1246 bp 5′‐flanking regions of the RHD and RHCE promoter, and found that the proximal cis ‐regulatory region of the RHD/RHCE promoter is 105 bp with binding motifs for Sp1, GATA‐1 and E2F transcription factors and a 55‐bp core devoid of known binding motifs.…”

Section: Introductionmentioning

confidence: 99%

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Polymorphisms in the promoter regions of RHD and RHCE genes in the Chinese Han population

Shao,

Zheng,

Zhou

et al. 2023

Vox Sanguinis

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Background and ObjectivesThe Rh blood group system is the most polymorphic human blood group system. Previous studies have investigated variants in the RHD and RHCE promoter. The relevance of these variants to the Chinese Han population is further clarified in this study.Materials and MethodsIn total, 317 donors (223 Rh D‐positive [D+], including 20 Del and 94 Rh D‐negative [D−]) were randomly selected. The promoter regions and exon 1 of RHD and RHCE were amplified through polymerase chain reaction (PCR) whose products were directly sequenced using forward and reverse primers.ResultsExpected PCR products of the RHD promoter and exon 1 were amplified in 223 D+ individuals, including 20 Del individuals, and were absent in 81 of 94 D− individuals. Expected PCR products of RHCE were observed in all donors. Two single nucleotide variants (SNVs) were observed in the RHD promoter region. Moreover, 11 SNVs were observed in the promoter and exon 1 of RHCE. rs4649082, rs2375313, rs2281179, rs2072933, rs2072932, rs2072931 and rs586178 with strong linkage disequilibria were significantly different between the D+ and D− groups. [A;C] was the most common haplotype in the RHD promoter (NC_000001.11:g.[−1033A>G;−831C>T]). [G;T;T;A;T;A;C;G;A;C;G] was the most predominant haplotype in both total and D− groups. In D+ individuals, [A;C;T;G;C;G;C;G;C;C;C] was the most frequent haplotype in the RHCE promoter (NC_000001.11:g.[−1080A>G;−958C>T;−390T>C;−378G>A;−369C>T;−296G>A;−144C>G;−132G>A;−122C>A;28C>T;48C>G]).ConclusionWe speculate that the SNVs/haplotypes found in this article cannot significantly affect gene expression. The present study findings should help elucidate the molecular basis of the polymorphic expression of RHD and RHCE promoter regions.

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“…Transient transfection experiments have shown that these are indispensable for the regulatory activity of the +5.8-kb site. 6,7,12 Deletion and single nucleotide substitutions in the RUNX motif have been found in individuals with A m , B 3 or B w , 8,9,12 while nucleotide substitutions in the downstream GATA motif have been reported in individuals with B m and A m 7,10,11 During erythroid differentiation of CD34 + cells into erythroid cells in vitro, it has been shown that reduction of RUNX1 and GATA2 corresponds to a decline of ABO expression in later stage, while there is no consistent relationship between ABO and GATA1. 13 Thus, it seems that RUNX1 and GATA2 play more important roles in A-or B-antigen expression during erythroid differentiation.…”

Section: Introductionmentioning

confidence: 99%

Reduction of blood group A antigen on erythrocytes in a patient with myelodysplastic syndrome harboring somatic mutations in RUNX1 and GATA2

et al. 2021

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Background: Reduction of blood group ABO antigens on red blood cells (RBCs) is well known in patients with leukemias, and this reduction of ABO expression is strongly associated with DNA methylation of the ABO promoter.Previously, we reported a two-nucleotide deletion in RUNX1 encoding an abnormally elongated protein lacking the trans-activation domain in a patient with myelodysplastic syndrome (MDS) showing A-antigen loss on RBCs. This prompted us to investigate the underlying mechanism responsible for A-antigen reduction on RBCs in another patient with MDS.Study Design and Methods: Screening of somatic mutations was carried out using a targeted sequencing panel with genomic DNA from peripheral blood mononuclear cells from the patient and eleven MDS controls without A-or Bantigen loss. DNA methylation of the ABO promoter was examined by bisulfite genomic sequencing. Transient transfection assays were performed for functional evaluation of mutations.Results: Screening of somatic mutations showed missense mutations in RUNX1 and GATA2 in the patient, while no mutation was found in exons of those genes in the controls. There was no significant difference in ABO promoter methylation between the patient and the controls. Transient transfection experiments into COS-7 and K562 cells suggested that the amino acid substitutions encoded by those mutations reduced or lost the trans-activation potential of the ABO expression. Conclusion: Considering the discrepancy between the variant frequencies of these mutations and the ratios of the RBCs with A-antigens loss, the antigen reduction might be associated with these somatic mutations and hypermethylation of the ABO promoter.COSMIC with accession numbers: COSP49519.

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Effect on gene expression of three allelic variants in GATA motifs of ABO, RHD, and RHCE regulatory elements

Abstract: Three new alleles in the ABO, RHD, and RHCE genes consist of single-nucleotide changes within GATA motifs, emphasizing the key role of GATA transcription factors in the expression of blood group genes.

Cited by 9 publications

References 20 publications

Emergence of an erythroid cell-specific regulatory region in ABO intron 1 attributable to A- or B-antigen expression on erythrocytes in Hominoidea

Emergence of an erythroid cell-specific regulatory region in ABO intron 1 attributable to A- or B-antigen expression on erythrocytes in Hominoidea

Polymorphisms in the promoter regions of RHD and RHCE genes in the Chinese Han population

Reduction of blood group A antigen on erythrocytes in a patient with myelodysplastic syndrome harboring somatic mutations in RUNX1 and GATA2

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