ArticleNucleic acids research2012
Targeted transcriptional activation of silent oct4 pluripotency gene by combining designer TALEs and inhibition of epigenetic modifiers.
Article in Nucleic acids research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers.
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100 citing papers in PubMed, 183 citations in OpenAlex.
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- CRISPR-Cas-mediated transcriptional control and epi-mutagenesis.Plant physiology · 2022Review
- Epigenetic features improve TALE target prediction.BMC genomics · 2021Article
- Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Chromatin Manipulation and Editing: Challenges, New Technologies and Their Use in Plants.International journal of molecular sciences · 2021Review
- Genome Editing Human Pluripotent Stem Cells to Model β-Cell Disease and Unmask Novel Genetic Modifiers.Frontiers in endocrinology · 2021Review
- Gene Therapy for Cardiovascular Disease: Basic Research and Clinical Prospects.Frontiers in cardiovascular medicine · 2021Review
- Functional Comparison between VP64-dCas9-VP64 and dCas9-VP192 CRISPR Activators in Human Embryonic Kidney Cells.International journal of molecular sciences · 2021Article
- Review
- Herpesviral lytic gene functions render the viral genome susceptible to novel editing by CRISPR/Cas9.eLife · 2019Article
- Programmable Nuclease-Based Integration into Novel Extragenic Genomic Safe Harbor Identified from Korean Population-Based CNV Analysis.Molecular therapy oncolytics · 2019Article
- The Chromatin Structure of CRISPR-Cas9 Target DNA Controls the Balance between Mutagenic and Homology-Directed Gene-Editing Events.Molecular therapy. Nucleic acids · 2019Article
- Therapeutic application of the CRISPR system: current issues and new prospects.Human genetics · 2019Review
40 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Specific control of gene activity is a valuable tool to study and engineer cellular functions. Recent studies uncovered the potential of transcription activator-like effector (TALE) proteins that can be tailored to activate user-defined target genes. It remains however unclear whether and how epigenetic modifications interfere with TALE-mediated transcriptional activation. We studied the activity of five designer TALEs (dTALEs) targeting the oct4 pluripotency gene. In vitro assays showed that the five dTALEs that target distinct sites in the oct4 promoter had the expected DNA specificity and comparable affinities to their corresponding DNA targets. In contrast to their similar in vitro properties, transcriptional activation of oct4 by these distinct dTALEs varied up to 25-fold. While dTALEs efficiently upregulated transcription of the active oct4 promoter in embryonic stem cells (ESCs) they failed to activate the silenced oct4 promoter in ESC-derived neural stem cells (NSCs), indicating that as for endogenous transcription factors also dTALE activity is limited by repressive epigenetic mechanisms. We therefore targeted the activity of epigenetic modulators and found that chemical inhibition of histone deacetylases by valproic acid or DNA methyltransferases by 5-aza-2'-deoxycytidine facilitated dTALE-mediated activation of the epigenetically silenced oct4 promoter in NSCs. Notably, demethylation of the oct4 promoter occurred only if chemical inhibitors and dTALEs were applied together but not upon treatment with inhibitors or dTALEs only. These results show that dTALEs in combination with chemical manipulation of epigenetic modifiers facilitate targeted transcriptional activation of epigenetically silenced target genes.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.