PREVENTION OF TRANSCRIPTIONAL γ-GLOBIN GENE SILENCING BY INDUCING THE HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN POINT MUTATION USING CHIMERAPLAST-MEDIATED GENE TARGETING

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RANJBARAN REZA; NIKOGOFTAR ZARIF MAHIN; SHARIFZADEH SEDIGHEH; GOLAFSHAN HABIBOLLAH; POURFATHOLLAH ALI AKBAR

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Journal: Cell Journal (Yakhteh) Year:2018 | Volume:20 | Issue:3 Page(s): 318-325

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Title

PREVENTION OF TRANSCRIPTIONAL γ-GLOBIN GENE SILENCING BY INDUCING THE HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN POINT MUTATION USING CHIMERAPLAST-MEDIATED GENE TARGETING

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Keywords

ERYTHROID PROGENITOR CELLS

GENE SILENCING

OLIGONUCLEOTIDE-DIRECTED MUTAGENESIS

Abstract

Objective: Hemoglobin F (HbF) augmentation is considered a clinically beneficial phenomenon in b-hemoglobinopathies. Prevention of γ-globin GENE SILENCING, inspired by the hereditary persistence of fetal hemoglobin, may be a suitable strategy to upregulate HbF expression in these patients. Therefore, our objective was to assess the potential feasibility of induced -117 G®Asubstitution in HBG promoter in prevention of transcriptional silencing of the g-globin.Materials and Methods: In this experimental study, human peripheral blood-derived hematopoietic stem cells (HSCs) and the K562 cell line were differentiated to erythroid cells. Erythroid maturation was examined using cell morphology parameters and flow cytometry analysis of CD235a expression. A synthesised chimeraplast was transfected to differentiating cells. The efficiency of chimeraplast delivery into target cells was assessed by flow cytometry. Restriction-fragment length polymorphism and DNA sequencing verified OLIGONUCLEOTIDE-DIRECTED MUTAGENESIS. Gene conversion frequency and globin genes expression was quantified through Allele specific-quantitaive polymerase chain reaction (AS-qPCR) and quantitative-PCR respectively.Results: Increase in CD235a-expressing cells along with observations made for different stages of erythroid maturation confirmed erythroid differentiation in HSCs and K562 cells.g to b-globin gene switching was estimated to be on days 18-21 of HSC differentiation. Flow cytometry analysis showed that more than 70% of ERYTHROID PROGENITOR CELLS (EPCs) were transfected with the chimeraplast. The highest gene conversion efficiency was 7.2 and 11.1% in EPCs and K562 cells respectively. The induced mutation led to a 1.97-fold decrease in b/g-globin gene expression in transfected EPCs at the experimental end point (day 28) whereas, due to the absence of b-globin gene expression following K562 differentiation, this rate was not evaluable.Conclusion: Our results suggest the effectiveness of chimeraplasty in induction of the mutation of interest in both EPCs and K562 cells. We also demonstrate that the single nucleotide promoter variant was able to significantly inhibit g-globingene silencing during erythroid differentiation.

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APA: Copy

RANJBARAN, REZA, NIKOGOFTAR ZARIF, MAHIN, SHARIFZADEH, SEDIGHEH, GOLAFSHAN, HABIBOLLAH, & POURFATHOLLAH, ALI AKBAR. (2018). PREVENTION OF TRANSCRIPTIONAL γ-GLOBIN GENE SILENCING BY INDUCING THE HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN POINT MUTATION USING CHIMERAPLAST-MEDIATED GENE TARGETING. CELL JOURNAL (YAKHTEH), 20(3), 318-325. SID. https://sid.ir/paper/714190/en

Vancouver: Copy

RANJBARAN REZA, NIKOGOFTAR ZARIF MAHIN, SHARIFZADEH SEDIGHEH, GOLAFSHAN HABIBOLLAH, POURFATHOLLAH ALI AKBAR. PREVENTION OF TRANSCRIPTIONAL γ-GLOBIN GENE SILENCING BY INDUCING THE HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN POINT MUTATION USING CHIMERAPLAST-MEDIATED GENE TARGETING. CELL JOURNAL (YAKHTEH)[Internet]. 2018;20(3):318-325. Available from: https://sid.ir/paper/714190/en

IEEE: Copy

REZA RANJBARAN, MAHIN NIKOGOFTAR ZARIF, SEDIGHEH SHARIFZADEH, HABIBOLLAH GOLAFSHAN, and ALI AKBAR POURFATHOLLAH, “PREVENTION OF TRANSCRIPTIONAL γ-GLOBIN GENE SILENCING BY INDUCING THE HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN POINT MUTATION USING CHIMERAPLAST-MEDIATED GENE TARGETING,” CELL JOURNAL (YAKHTEH), vol. 20, no. 3, pp. 318–325, 2018, [Online]. Available: https://sid.ir/paper/714190/en

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