Activation of Fetal γ-globin Gene Expression via Direct Protein Delivery of Synthetic Zinc-finger DNA-Binding Domains

Mir A. Hossain, Yong Shen, Isaac Knudson, Shaleen Thakur, Jared R. Stees, Yi Qiu, Betty Sue Pace, Kenneth R. Peterson, Jörg Bungert

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Reactivation of γ-globin expression has been shown to ameliorate disease phenotypes associated with mutations in the adult β-globin gene, including sickle cell disease. Specific mutations in the promoter of the γ-globin genes are known to prevent repression of the genes in the adult and thus lead to hereditary persistence of fetal hemoglobin. One such hereditary persistence of fetal hemoglobin is associated with a sequence located 567 bp upstream of the Gγ-globin gene which assembles a GATA-containing repressor complex. We generated two synthetic zinc-finger DNA-binding domains (ZF-DBDs) targeting this sequence. The -567Gγ ZF-DBDs associated with high affinity and specificity with the target site in the γ-globin gene promoter. We delivered the -567Gγ ZF-DBDs directly to primary erythroid cells. Exposure of these cells to the recombinant -567Gγ ZF-DBDs led to increased expression of the γ-globin gene. Direct protein delivery of ZF-DBDs that compete with transcription regulatory proteins will have broad implications for modulating gene expression in analytical or therapeutic settings.

Original languageEnglish (US)
Pages (from-to)e378
JournalMolecular Therapy - Nucleic Acids
Volume5
DOIs
StatePublished - Jan 1 2016

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Globins
Zinc Fingers
Gene Expression
DNA
Fetal Hemoglobin
Proteins
Genes
Erythroid Cells
Mutation
Sickle Cell Anemia
Phenotype

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Activation of Fetal γ-globin Gene Expression via Direct Protein Delivery of Synthetic Zinc-finger DNA-Binding Domains. / Hossain, Mir A.; Shen, Yong; Knudson, Isaac; Thakur, Shaleen; Stees, Jared R.; Qiu, Yi; Pace, Betty Sue; Peterson, Kenneth R.; Bungert, Jörg.

In: Molecular Therapy - Nucleic Acids, Vol. 5, 01.01.2016, p. e378.

Research output: Contribution to journalArticle

Hossain, Mir A. ; Shen, Yong ; Knudson, Isaac ; Thakur, Shaleen ; Stees, Jared R. ; Qiu, Yi ; Pace, Betty Sue ; Peterson, Kenneth R. ; Bungert, Jörg. / Activation of Fetal γ-globin Gene Expression via Direct Protein Delivery of Synthetic Zinc-finger DNA-Binding Domains. In: Molecular Therapy - Nucleic Acids. 2016 ; Vol. 5. pp. e378.
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