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

2016 ◽  
Vol 5 ◽  
pp. e378 ◽  
Author(s):  
Mir A Hossain ◽  
Yong Shen ◽  
Isaac Knudson ◽  
Shaleen Thakur ◽  
Jared R Stees ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Zinc Finger ◽  
Protein Delivery ◽  
Globin Gene ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Globin Gene Expression

scholarly journals Artificial Zinc Finger DNA Binding Domains: Versatile Tools for Genome Engineering and Modulation of Gene Expression

2015 ◽  
Vol 116 (11) ◽  
pp. 2435-2444 ◽  
Author(s):  
Mir A. Hossain ◽  
Joeva J. Barrow ◽  
Yong Shen ◽  
MD Imdadul Haq ◽  
Jörg Bungert
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Zinc Finger ◽  
Genome Engineering ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Modulation Of Gene Expression

scholarly journals The Role of Zinc Finger Linkers in Zinc Finger Protein Binding to DNA

2020 ◽  
Author(s):  
Mazen Hamed ◽  
Reema Siam ◽  
Roza Zaid
Keyword(s):  
Amino Acid ◽  
Dna Binding ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Md Simulations ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Finger Protein ◽  
The Right

Zinc finger proteins (ZFP) play important roles in cellular processes. The DNA binding region of ZFP consists of 3 zinc finger DNA binding domains connected by amino acid linkers, the sequence TGQKP connects ZF1 and ZF2, and TGEKP connects ZF2 with ZF3. Linkers act to tune the zinc finger protein in the right position to bind its DNA target, the type of amino acid residues and length of linkers reflect on ZF1-ZF2-ZF3 interactions and contribute to the search and recognition process of ZF protein to its DNA target. Linker mutations and the affinity of the resulting mutants to specific and nonspecific DNA targets were studied by MD simulations and MM_GB(PB)SA. The affinity of mutants to DNA varied with type and position of amino acid residue. Mutation of K in TGQKP resulted in loss in affinity due to the loss of positive K interaction with phosphates, mutation of G showed loss in affinity to DNA, WT protein and all linker mutants showed loss in affinity to a nonspecific DNA target, this finding confirms previous reports which interpreted this loss in affinity as due to ZF1 having an anchoring role, and ZF3 playing an explorer role in the binding mechanism. The change in ZFP-DNA affinity with linker mutations is discussed in view of protein structure and role of linker residues in binding.

scholarly journals Control of bacterial anti-phage signaling by a WYL domain transcription factor

2022 ◽  
Author(s):  
Chelsea L Blankenchip ◽  
Justin V Nguyen ◽  
Rebecca K Lau ◽  
Qiaozhen Ye ◽  
Yajie Gu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dna Binding ◽  
Promoter Region ◽  
Bound State ◽  
Signaling Proteins ◽  
Abortive Infection ◽  
Immune Systems ◽  
Dna Binding Domains ◽  
Binding Domains

Bacteria use diverse immune systems to defend themselves from ubiquitous viruses termed bacteriophages (phages). Many anti-phage systems function by abortive infection to kill a phage-infected cell, raising the question of how these systems are regulated to avoid activation and cell killing outside the context of infection. Here, we identify a transcription factor associated with the widespread CBASS bacterial immune system, that we term CapW. CapW forms a homodimer and binds a palindromic DNA sequence in the CBASS promoter region. Two crystal structures of CapW reveal how the protein switches from a DNA binding-competent state to a ligand-bound state that cannot bind DNA due to misalignment of dimer-related DNA binding domains. We show that CapW strongly represses CBASS gene expression in uninfected cells, and that CapW disruption likely results in toxicity due to uncontrolled CBASS expression. Our results parallel recent findings with BrxR, a transcription factor associated with the BREX anti-phage system, and suggest that CapW and BrxR are the founding members of a family of universal anti-phage signaling proteins.

Base sequence discrimination by zinc-finger DNA-binding domains

Nature ◽  
1991 ◽  
Vol 349 (6305) ◽  
pp. 175-178 ◽  
Author(s):  
Jeannette Nardelli ◽  
Toby J. Gibson ◽  
Christine Vesque ◽  
Patrick Charnay
Keyword(s):  
Dna Binding ◽  
Zinc Finger ◽  
Base Sequence ◽  
Dna Binding Domains ◽  
Binding Domains

scholarly journals Induction of Fetal HemoglobinIn VivoMediated by a Syntheticγ-Globin Zinc Finger Activator

Anemia ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Flávia C. Costa ◽  
Halyna Fedosyuk ◽  
Renee Neades ◽  
Johana Bravo de Los Rios ◽  
Carlos F. Barbas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Zinc Finger ◽  
Yeast Artificial Chromosome ◽  
Bone Marrow Cells ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Proximal Promoter ◽  
Erythroid Progenitor ◽  
Globin Gene Expression

Sickle cell disease (SCD) andβ-thalassemia patients are phenotypically normal if they carry compensatory hereditary persistence of fetal hemoglobin (HPFH) mutations that result in increased levels of fetal hemoglobin (HbF,γ-globin chains) in adulthood. Thus, research has focused on manipulating the reactivation ofγ-globin gene expression during adult definitive erythropoiesis as the most promising therapy to treat these hemoglobinopathies. Artificial transcription factors (ATFs) are synthetic proteins designed to bind at a specific DNA sequence and modulate gene expression. The artificial zinc finger gg1-VP64 was designed to target the −117 region of theAγ-globin gene proximal promoter and activate expression of this gene. Previous studies demonstrated that HbF levels were increased in murine chemical inducer of dimerization (CID)-dependent bone marrow cells carrying a humanβ-globin locus yeast artificial chromosome (β-YAC) transgene and in CD34+erythroid progenitor cells from normal donors andβ-thalassemia patients. Herein, we report that gg1-VP64 increasedγ-globin gene expressionin vivo, in peripheral blood samples from gg1-VP64β-YAC double-transgenic (bigenic) mice. Our results demonstrate that ATFs function in an animal model to increase gene expression. Thus, this class of reagent may be an effective gene therapy for treatment of some inherited diseases.

scholarly journals Male-specific Fruitless isoforms have different regulatory roles conferred by distinct zinc finger DNA binding domains

BMC Genomics ◽  
2013 ◽  
Vol 14 (1) ◽  
pp. 659 ◽  
Author(s):  
Justin E Dalton ◽  
Justin M Fear ◽  
Simon Knott ◽  
Bruce S Baker ◽  
Lauren M McIntyre ◽  
...  
Keyword(s):  
Dna Binding ◽  
Zinc Finger ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Male Specific

scholarly journals Differential abilities to engage inaccessible chromatin diversify vertebrate HOX binding patterns

2019 ◽  
Author(s):  
Milica Bulajić ◽  
Divyanshi Srivastava ◽  
Jeremy S Dasen ◽  
Hynek Wichterle ◽  
Shaun Mahony ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Dna Binding Domain ◽  
Regulatory Activity ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Posterior Group ◽  
Differential Gene ◽  
Domain Similarity

ABSTRACTWhile Hox genes encode for conserved transcription factors (TFs), they are further divided into anterior, central, and posterior groups based on their DNA-binding domain similarity. The posterior Hox group expanded in the deuterostome clade and patterns caudal and distal structures. We aim to address how similar HOX TFs diverge to induce different positional identities. We studied HOX TF DNA-binding and regulatory activity during an in vitro motor neuron differentiation system that recapitulates embryonic development. We find diversity in the genomic binding profiles of different HOX TFs, even among the posterior group paralogs that share similar DNA binding domains. These differences in genomic binding are explained by differing abilities to bind to previously inaccessible sites. For example, the posterior group HOXC9 has a greater ability to bind occluded sites than the posterior HOXC10, producing different binding patterns and driving differential gene expression programs. From these results, we propose that the differential abilities of posterior HOX TFs to bind to previously inaccessible chromatin drive patterning diversification.

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