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 language | English (US) |
|---|---|
| Pages (from-to) | e378 |
| Journal | Molecular Therapy - Nucleic Acids |
| Volume | 5 |
| DOIs | |
| State | Published - Jan 1 2016 |
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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 journal › Article
}
TY - JOUR
T1 - Activation of Fetal γ-globin Gene Expression via Direct Protein Delivery of Synthetic Zinc-finger DNA-Binding Domains
AU - Hossain, Mir A.
AU - Shen, Yong
AU - Knudson, Isaac
AU - Thakur, Shaleen
AU - Stees, Jared R.
AU - Qiu, Yi
AU - Pace, Betty Sue
AU - Peterson, Kenneth R.
AU - Bungert, Jörg
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85015234665&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85015234665&partnerID=8YFLogxK
U2 - 10.1038/mtna.2016.85
DO - 10.1038/mtna.2016.85
M3 - Article
AN - SCOPUS:85015234665
VL - 5
SP - e378
JO - Molecular Therapy - Nucleic Acids
JF - Molecular Therapy - Nucleic Acids
SN - 2162-2531
ER -