TALE-mediated modulation of transcriptional enhancers in vivo

Crocker, Justin; Stern, David L.

doi:10.1038/nmeth.2543

Cited by 77 publications

(61 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While the resulting changes in expression, particularly in case of our TALE-VP64 transcription factor, were modest, our results mark a significant extension from the previously reported epigenomic editing of Drosophila enhancers located within 10kb from their target genes(Crocker and Stern, 2013). We predict that the molecular toolbox for future treatments of cognitive and psychiatric disease will include targeted editing of long-range enhancer elements regulating gene expression critical for neuronal plasticity and behavior.…”

Section: Discussionsupporting

confidence: 60%

Conserved Higher-Order Chromatin Regulates NMDA Receptor Gene Expression and Cognition

Bharadwaj

Peter

Jiang

et al. 2014

Neuron

104

View full text Add to dashboard Cite

3-dimensional chromosomal conformations regulate transcription by moving enhancers and regulatory elements into spatial proximity with target genes. Here, we describe activity-regulated long-range loopings bypassing up to 0.5 megabase of linear genome to modulate NMDA glutamate receptor GRIN2B expression in human and mouse prefrontal cortex. Distal intronic and 3’ intergenic loop formations competed with repressor elements to access promoter-proximal sequences, and facilitated expression via a ‘cargo’ of AP-1 and NRF-1 transcription factors and TALE-based transcriptional activators. Neuronal deletion or overexpression of Kmt2a/Mll1 H3K4- and Kmt1e/Setdb1 H3K9-methyltransferase was associated with higher order chromatin changes at distal regulatory Grin2b sequences and impairments in working memory. Genetic polymorphisms and isogenic deletions of loop-bound sequences conferred liability for cognitive performance and decreased GRIN2B expression. Dynamic regulation of chromosomal conformations emerges as a novel layer for transcriptional mechanisms impacting neuronal signaling and cognition.

show abstract

Section: Discussionsupporting

confidence: 60%

Conserved Higher-Order Chromatin Regulates NMDA Receptor Gene Expression and Cognition

Bharadwaj

Peter

Jiang

et al. 2014

Neuron

104

View full text Add to dashboard Cite

show abstract

“…TALE repressors have been used to successfully suppress multiple endogenous genes in human cells (82), model organisms (83), and plants (84). In addition to targeting endogenous genes, TALE repressors are valuable tools for the development of synthetic gene circuits (21, 22).…”

Section: Synthetic Repressorsmentioning

confidence: 99%

Engineering synthetic TALE and CRISPR/Cas9 transcription factors for regulating gene expression

Kabadi

Gersbach

2014

Methods

View full text Add to dashboard Cite

Engineered DNA-binding proteins that can be targeted to specific sites in the genome to manipulate gene expression have enabled many advances in biomedical research. This includes generating tools to study fundamental aspects of gene regulation and the development of a new class of gene therapies that alter the expression of endogenous genes. Designed transcription factors have entered clinical trials for the treatment of human diseases and others are in preclinical development. High-throughput and user-friendly platforms for designing synthetic DNA-binding proteins present innovative methods for deciphering cell biology and designing custom synthetic gene circuits. We review two platforms for designing synthetic transcription factors for manipulating gene expression: Transcription Activator-Like Effectors (TALEs) and the RNA-guided Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system. We present an overview of each technology and a guide for designing and assembling custom TALE- and CRISPR/Cas9-based transcription factors. We also discuss characteristics of each platform that are best suited for different applications.

show abstract

“…In the case of Cas9, the catalytically inactive mutant form of Cas9 (referred to as dCas9 [40]), which contained two mutations of the RuvC1 and HNH nuclease domains can be used for RNA-mediated custom-designed transcriptional factors. Currently, gene fusions of TALEs/dCas9 to several types of activation/repression domains are available for gene regulation tools in many organisms including mammalians and plants [64][65][66]. Piatek et al [67] demonstrated the target-specific gene regulation using dCas9-based transcriptional activator and repressor in tobacco.…”

Section: Molecular Breeding: Genomics and Genetic Engineering In Woodmentioning

confidence: 99%

Genome engineering of woody plants: past, present and future

2016

View full text Add to dashboard Cite

Engineered endonucleases that digest the specific sequences can be used to modify target genomes precisely. This is called ''genome editing'' and is used widely to modify the genome of various organisms. The DNA-binding domains of zinc finger (ZF) proteins were the first to be used as a genome editing tool, in the form of designed ZF nucleases and, more recently, transcription activator-like effector as well as the clustered, regularly interspaced, short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9) system that targets RNA-DNA rather than protein-DNA interactions have been used successfully. These are powerful tools with which targeted gene modifications can be introduced in various organisms, including various plant species. A key step in genome editing is the generation of a double-stranded DNA break that is specific to the target gene. This is achieved using custom-designed endonucleases, which enable site-directed mutagenesis via a non-homologous end joining repair pathway and/or gene targeting via homologous recombination to occur efficiently at specific sites in the genome. This review provides an overview of the current status of genomics and genetic engineering of woody plants, and recent advances in genome editing technologies in plants as well as fungi. We also discuss how these strategies can provide insights into molecular breeding technology for woody plants.

show abstract

TALE-mediated modulation of transcriptional enhancers in vivo

Cited by 77 publications

References 41 publications

Conserved Higher-Order Chromatin Regulates NMDA Receptor Gene Expression and Cognition

Conserved Higher-Order Chromatin Regulates NMDA Receptor Gene Expression and Cognition

Engineering synthetic TALE and CRISPR/Cas9 transcription factors for regulating gene expression

Genome engineering of woody plants: past, present and future

Contact Info

Product

Resources

About