Reprogramming cell fate with artificial transcription factors

Heiderscheit, Evan A.; Eguchi, Asuka; Spurgat, Mackenzie C.; Ansari, Aseem Z.

doi:10.1002/1873-3468.12993

Cited by 15 publications

(19 citation statements)

References 129 publications

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“…The ability to modify a hairpin Py-Im polyamide while maintaining specificity in a chromatinized environment is an encouraging finding for application as synthetic transcription factors (Syn-TFs). Syn-TFs comprise a modular DNA-binding domain directly fused to or designed to recruit a regulatory domain capable of modulating gene expression when localized to genomic regulatory elements [ 58 , 59 ]. Protein-based artificial TFs have been developed based on zinc finger proteins (ZFPs), transcription activator-like effectors (TALEs), and the clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) system [ 58 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

“…Syn-TFs comprise a modular DNA-binding domain directly fused to or designed to recruit a regulatory domain capable of modulating gene expression when localized to genomic regulatory elements [ 58 , 59 ]. Protein-based artificial TFs have been developed based on zinc finger proteins (ZFPs), transcription activator-like effectors (TALEs), and the clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) system [ 58 , 59 ]. However, these methods may be limited by the lack of an efficient delivery mechanism, in vivo bioavailability and unknown immunogenic factors [ 60 – 62 ].…”

Section: Discussionmentioning

confidence: 99%

“…clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) system [58,59]. However, these methods may be limited by the lack of an efficient delivery mechanism, in vivo bioavailability and unknown immunogenic factors [60][61][62].…”

Section: Plos Onementioning

confidence: 99%

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Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome

Finn

Bhimsaria²,

Ali

et al. 2020

PLoS ONE

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Pyrrole–imidazole (Py–Im) polyamides are synthetic molecules that can be rationally designed to target specific DNA sequences to both disrupt and recruit transcriptional machinery. While in vitro binding has been extensively studied, in vivo effects are often difficult to predict using current models of DNA binding. Determining the impact of genomic architecture and the local chromatin landscape on polyamide-DNA sequence specificity remains an unresolved question that impedes their effective deployment in vivo. In this report we identified polyamide–DNA interaction sites across the entire genome, by covalently crosslinking and capturing these events in the nuclei of human LNCaP cells. This technique confirms the ability of two eight ring hairpin-polyamides, with similar architectures but differing at a single ring position (Py to Im), to retain in vitro specificities and display distinct genome-wide binding profiles.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome

Finn

Bhimsaria²,

Ali

et al. 2020

PLoS ONE

Self Cite

View full text Add to dashboard Cite

show abstract

“…The ability to modify a hairpin Py-Im polyamide while maintaining specificity in a chromatinized environment is an encouraging finding for application as synthetic transcription factors (Syn-TFs). Syn-TFs comprise a modular DNA-binding domain directly fused to or designed to recruit a regulatory domain capable of modulating gene expression when localized to genomic regulatory elements [57,58]. Protein-based artificial TFs have been developed based on zinc finger proteins (ZFPs), transcription activator-like effectors (TALEs), and the clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) system [57,58].…”

Section: Genomic Occupancy Correlates With Binding Predictions Based mentioning

confidence: 99%

Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome

Finn¹,

Bhimsaria²,

Ali³

et al. 2020

Preprint

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Regulating desired loci in the genome with sequence specific DNA binding molecules is a major goal for the development of precision medicine. Pyrrole imidazole (Py Im) polyamides are synthetic molecules that can be rationally designed to target specific DNA sequences to both disrupt and recruit transcriptional machinery. While in vitro binding has been extensively studied, in vivo effects are often difficult to predict using current models of DNA binding. Determining the impact of genomic architecture and the local chromatin landscape on polyamide DNA sequence specificity remains an unresolved question that impedes their effective deployment in vivo. In this report we identified polyamide DNA interaction sites across the entire genome, by covalently crosslinking and capturing these events in the nuclei of human LNCaP cells. This method, termed COSMIC seq, confirms the ability of hairpin polyamides, with similar architectures but differing at a single ring position, to retain in vitro specificities and display distinct genome-wide binding profiles. These results underpin the development of Py Im polyamides as DNA targeting molecules that mediate their regulatory or remedial functions at desired genomic loci.

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“…The artificial transcription factors (ATFs) are molecular tools that can manage the gene expression to induce changes in different cell stages ( 13 , 14 ). Within the different types of ATFs, the emerging CRISPR-dCas9-based ATFs have been used to precisely regulate gene expression in different in vitro and in vivo studies.…”

Section: Introductionmentioning

confidence: 99%

CRISPR-dCas9-Based Artificial Transcription Factors to Improve Efficacy of Cancer Treatment With Drug Repurposing: Proposal for Future Research

2021

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Due to the high resistance that cancer has shown to conventional therapies, it is difficult to treat this disease, particularly in advanced stages. In recent decades, treatments have been improved, being more specific according to the characteristics of the tumor, becoming more effective, less toxic, and invasive. Cancer can be treated by the combination of surgery, radiation therapy, and/or drug administration, but therapies based on anticancer drugs are the main cancer treatment. Cancer drug development requires long-time preclinical and clinical studies and is not cost-effective. Drug repurposing is an alternative for cancer therapies development since it is faster, safer, easier, cheaper, and repurposed drugs do not have serious side effects. However, cancer is a complex, heterogeneous, and highly dynamic disease with multiple evolving molecular constituents. This tumor heterogeneity causes several resistance mechanisms in cancer therapies, mainly the target mutation. The CRISPR-dCas9-based artificial transcription factors (ATFs) could be used in cancer therapy due to their possibility to manipulate DNA to modify target genes, activate tumor suppressor genes, silence oncogenes, and tumor resistance mechanisms for targeted therapy. In addition, drug repurposing combined with the use of CRISPR-dCas9-based ATFs could be an alternative cancer treatment to reduce cancer mortality. The aim of this review is to describe the potential of the repurposed drugs combined with CRISPR-dCas9-based ATFs to improve the efficacy of cancer treatment, discussing the possible advantages and disadvantages.

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Reprogramming cell fate with artificial transcription factors

Cited by 15 publications

References 129 publications

Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome

Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome

Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome

CRISPR-dCas9-Based Artificial Transcription Factors to Improve Efficacy of Cancer Treatment With Drug Repurposing: Proposal for Future Research

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