Functional analysis of a novel KLF1 gene promoter variation associated with hereditary persistence of fetal hemoglobin
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2013
Authors
Ugrin, MilenaZukić, Branka
Stojiljković, Maja
Bartsakoulia, Marina
Stanković, Biljana
Kotur, Nikola
Dokmanović, Lidija
Georgitsi, Marianthi
Patrinos, George P.
Pavlović, Sonja
Article (Published version)
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Show full item recordAbstract
Hereditary persistence of fetal hemoglobin (HPFH) is a rare hereditary condition resulting in elevated levels of fetal hemoglobin (HbF) in adults. Typical HPFH is associated with promoter mutations or large deletions affecting the human fetal globin (HBG1 and HBG2) genes, while genetic defects in other genes involved in human erythropoiesis, e.g. KLF1, also result in atypical HPFH. Here, we report the first KLF1 gene promoter mutation (KLF1:g.-148G gt A) that is associated with increased HbF level. This mutation was shown to result in drastically reduced CAT reporter gene expression in K562 cells, compared to the wild-type sequence (p = 0.009) and also in reduced KLF1 gene expression in vivo. Furthermore, consistent with in silico analysis, electrophoretic mobility shift analysis showed that the KLF1:g.-148G gt A mutation resides in a Sp1 binding site and further that this mutation leads to the ablation of Sp1 binding in vitro. These data suggest that the KLF1:g-148G gt A mutatio...n could play a role in increasing HbF levels in adults and further underlines the role of KLF1 as one of the key transcription factors involved in human fetal globin gene switching.
Keywords:
Transcription / Sp1 / Promoter mutation / KLF1 gene / Hereditary persistence of fetal hemoglobin / Fetal hemoglobinSource:
Annals of Hematology, 2013, 92, 1, 53-58Publisher:
- Springer, New York
Funding / projects:
- Research Promotion Foundation (Cyprus) [PiDeltaE046_02]
- European Commission [International Thalassemia Network (ITHANET)] [026539]
- Rare Diseases:Molecular Pathophysiology, Diagnostic and Therapeutic Modalities and Social, Ethical and Legal Aspects (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41004)
DOI: 10.1007/s00277-012-1625-9
ISSN: 0939-5555
PubMed: 23161389
WoS: 000313068700007
Scopus: 2-s2.0-84872356152
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Institution/Community
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Ugrin, Milena AU - Zukić, Branka AU - Stojiljković, Maja AU - Bartsakoulia, Marina AU - Stanković, Biljana AU - Kotur, Nikola AU - Dokmanović, Lidija AU - Georgitsi, Marianthi AU - Patrinos, George P. AU - Pavlović, Sonja PY - 2013 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/617 AB - Hereditary persistence of fetal hemoglobin (HPFH) is a rare hereditary condition resulting in elevated levels of fetal hemoglobin (HbF) in adults. Typical HPFH is associated with promoter mutations or large deletions affecting the human fetal globin (HBG1 and HBG2) genes, while genetic defects in other genes involved in human erythropoiesis, e.g. KLF1, also result in atypical HPFH. Here, we report the first KLF1 gene promoter mutation (KLF1:g.-148G gt A) that is associated with increased HbF level. This mutation was shown to result in drastically reduced CAT reporter gene expression in K562 cells, compared to the wild-type sequence (p = 0.009) and also in reduced KLF1 gene expression in vivo. Furthermore, consistent with in silico analysis, electrophoretic mobility shift analysis showed that the KLF1:g.-148G gt A mutation resides in a Sp1 binding site and further that this mutation leads to the ablation of Sp1 binding in vitro. These data suggest that the KLF1:g-148G gt A mutation could play a role in increasing HbF levels in adults and further underlines the role of KLF1 as one of the key transcription factors involved in human fetal globin gene switching. PB - Springer, New York T2 - Annals of Hematology T1 - Functional analysis of a novel KLF1 gene promoter variation associated with hereditary persistence of fetal hemoglobin EP - 58 IS - 1 SP - 53 VL - 92 DO - 10.1007/s00277-012-1625-9 ER -
@article{ author = "Ugrin, Milena and Zukić, Branka and Stojiljković, Maja and Bartsakoulia, Marina and Stanković, Biljana and Kotur, Nikola and Dokmanović, Lidija and Georgitsi, Marianthi and Patrinos, George P. and Pavlović, Sonja", year = "2013", abstract = "Hereditary persistence of fetal hemoglobin (HPFH) is a rare hereditary condition resulting in elevated levels of fetal hemoglobin (HbF) in adults. Typical HPFH is associated with promoter mutations or large deletions affecting the human fetal globin (HBG1 and HBG2) genes, while genetic defects in other genes involved in human erythropoiesis, e.g. KLF1, also result in atypical HPFH. Here, we report the first KLF1 gene promoter mutation (KLF1:g.-148G gt A) that is associated with increased HbF level. This mutation was shown to result in drastically reduced CAT reporter gene expression in K562 cells, compared to the wild-type sequence (p = 0.009) and also in reduced KLF1 gene expression in vivo. Furthermore, consistent with in silico analysis, electrophoretic mobility shift analysis showed that the KLF1:g.-148G gt A mutation resides in a Sp1 binding site and further that this mutation leads to the ablation of Sp1 binding in vitro. These data suggest that the KLF1:g-148G gt A mutation could play a role in increasing HbF levels in adults and further underlines the role of KLF1 as one of the key transcription factors involved in human fetal globin gene switching.", publisher = "Springer, New York", journal = "Annals of Hematology", title = "Functional analysis of a novel KLF1 gene promoter variation associated with hereditary persistence of fetal hemoglobin", pages = "58-53", number = "1", volume = "92", doi = "10.1007/s00277-012-1625-9" }
Ugrin, M., Zukić, B., Stojiljković, M., Bartsakoulia, M., Stanković, B., Kotur, N., Dokmanović, L., Georgitsi, M., Patrinos, G. P.,& Pavlović, S.. (2013). Functional analysis of a novel KLF1 gene promoter variation associated with hereditary persistence of fetal hemoglobin. in Annals of Hematology Springer, New York., 92(1), 53-58. https://doi.org/10.1007/s00277-012-1625-9
Ugrin M, Zukić B, Stojiljković M, Bartsakoulia M, Stanković B, Kotur N, Dokmanović L, Georgitsi M, Patrinos GP, Pavlović S. Functional analysis of a novel KLF1 gene promoter variation associated with hereditary persistence of fetal hemoglobin. in Annals of Hematology. 2013;92(1):53-58. doi:10.1007/s00277-012-1625-9 .
Ugrin, Milena, Zukić, Branka, Stojiljković, Maja, Bartsakoulia, Marina, Stanković, Biljana, Kotur, Nikola, Dokmanović, Lidija, Georgitsi, Marianthi, Patrinos, George P., Pavlović, Sonja, "Functional analysis of a novel KLF1 gene promoter variation associated with hereditary persistence of fetal hemoglobin" in Annals of Hematology, 92, no. 1 (2013):53-58, https://doi.org/10.1007/s00277-012-1625-9 . .