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New approaches to manipulating the epigenome.

Day JJ - Dialogues Clin Neurosci (2014)

Bottom Line: This improved control promises to revolutionize our understanding of epigenetic modifications in human health and disease states.Abstract available from the publisher.

View Article: PubMed Central - PubMed

Affiliation: Assistant Professor, Department of Neurobiology, University of Alabama at Birmingham, Alabama, USA.

ABSTRACT
Cellular processes that control transcription of genetic information are critical for cellular function, and are often implicated in psychiatric and neurological disease states. Among the most critical of these processes are epigenetic mechanisms, which serve to link the cellular environment with genomic material. Until recently our understanding of epigenetic mechanisms has been limited by the lack of tools that can selectively manipulate the epigenome with genetic, cellular, and temporal precision, which in turn diminishes the potential impact of epigenetic processes as therapeutic targets. This review highlights an emerging suite of tools that enable robust yet selective interrogation of the epigenome. In addition to allowing site-specific epigenetic editing, these tools can be paired with optogenetic approaches to provide temporal control over epigenetic processes, allowing unparalleled insight into the function of these mechanisms. This improved control promises to revolutionize our understanding of epigenetic modifications in human health and disease states.

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Related in: MedlinePlus

Sequence-specific gene modulation with designer DNA targeting tools. (A) transcriptional-activator like effectors (TALE) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas approaches are used to bind specific DNA sequences and serve as genomic anchors. TALEs use engineered protein sequences to confer sequence-specific binding to a targeted DNA site, whereas CRISPR accomplished this via a single guide RNA, which serves as a scaffold to recruit Cas9. With either approach, selected effector proteins that modulate gene function can be fused to engineered machinery, thereby providing localization to specific gene targets. (B) Fusion of generic transcriptional activators (left) or repressors (right) to sequence-specific machinery (shown here with the CRISPR/Cas system) results in selective gene expression modulation.
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DialoguesClinNeurosci-16-345-g001: Sequence-specific gene modulation with designer DNA targeting tools. (A) transcriptional-activator like effectors (TALE) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas approaches are used to bind specific DNA sequences and serve as genomic anchors. TALEs use engineered protein sequences to confer sequence-specific binding to a targeted DNA site, whereas CRISPR accomplished this via a single guide RNA, which serves as a scaffold to recruit Cas9. With either approach, selected effector proteins that modulate gene function can be fused to engineered machinery, thereby providing localization to specific gene targets. (B) Fusion of generic transcriptional activators (left) or repressors (right) to sequence-specific machinery (shown here with the CRISPR/Cas system) results in selective gene expression modulation.

Mentions: The recent emergence of approaches that allow tailored editing of the epigenome with the requirements outlined above has been possible in part due to enormous advances in genetic engineering. A common feature of new epigenetic tools is that they employ unique DNA sequences as a molecular homing device for secondary effector proteins that are capable of robust epigenetic reorganization. At the forefront of these approaches are tools built upon the nucleotide sequence recognition capacities native to three different systems: zinc-finger nucleases (ZFNs), transcriptional-activator like effectors (TALEs), and clustered regularly interspaced short palindromic repeats (CRISPR), which interact with Cas9 nucleases. Although these simple biochemical systems evolved for very different purposes, each employ an innate ability to recognize and bind specific DNA sequences, and each can be readily re-engineered to utilize this capacity for interrogation of the epigenome Figure 1. This review will highlight TALE and CRISPR-based approaches, given their recent emergence, ease of synthesis, and increased efficiency over ZFNs.


New approaches to manipulating the epigenome.

Day JJ - Dialogues Clin Neurosci (2014)

Sequence-specific gene modulation with designer DNA targeting tools. (A) transcriptional-activator like effectors (TALE) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas approaches are used to bind specific DNA sequences and serve as genomic anchors. TALEs use engineered protein sequences to confer sequence-specific binding to a targeted DNA site, whereas CRISPR accomplished this via a single guide RNA, which serves as a scaffold to recruit Cas9. With either approach, selected effector proteins that modulate gene function can be fused to engineered machinery, thereby providing localization to specific gene targets. (B) Fusion of generic transcriptional activators (left) or repressors (right) to sequence-specific machinery (shown here with the CRISPR/Cas system) results in selective gene expression modulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214177&req=5

DialoguesClinNeurosci-16-345-g001: Sequence-specific gene modulation with designer DNA targeting tools. (A) transcriptional-activator like effectors (TALE) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas approaches are used to bind specific DNA sequences and serve as genomic anchors. TALEs use engineered protein sequences to confer sequence-specific binding to a targeted DNA site, whereas CRISPR accomplished this via a single guide RNA, which serves as a scaffold to recruit Cas9. With either approach, selected effector proteins that modulate gene function can be fused to engineered machinery, thereby providing localization to specific gene targets. (B) Fusion of generic transcriptional activators (left) or repressors (right) to sequence-specific machinery (shown here with the CRISPR/Cas system) results in selective gene expression modulation.
Mentions: The recent emergence of approaches that allow tailored editing of the epigenome with the requirements outlined above has been possible in part due to enormous advances in genetic engineering. A common feature of new epigenetic tools is that they employ unique DNA sequences as a molecular homing device for secondary effector proteins that are capable of robust epigenetic reorganization. At the forefront of these approaches are tools built upon the nucleotide sequence recognition capacities native to three different systems: zinc-finger nucleases (ZFNs), transcriptional-activator like effectors (TALEs), and clustered regularly interspaced short palindromic repeats (CRISPR), which interact with Cas9 nucleases. Although these simple biochemical systems evolved for very different purposes, each employ an innate ability to recognize and bind specific DNA sequences, and each can be readily re-engineered to utilize this capacity for interrogation of the epigenome Figure 1. This review will highlight TALE and CRISPR-based approaches, given their recent emergence, ease of synthesis, and increased efficiency over ZFNs.

Bottom Line: This improved control promises to revolutionize our understanding of epigenetic modifications in human health and disease states.Abstract available from the publisher.

View Article: PubMed Central - PubMed

Affiliation: Assistant Professor, Department of Neurobiology, University of Alabama at Birmingham, Alabama, USA.

ABSTRACT
Cellular processes that control transcription of genetic information are critical for cellular function, and are often implicated in psychiatric and neurological disease states. Among the most critical of these processes are epigenetic mechanisms, which serve to link the cellular environment with genomic material. Until recently our understanding of epigenetic mechanisms has been limited by the lack of tools that can selectively manipulate the epigenome with genetic, cellular, and temporal precision, which in turn diminishes the potential impact of epigenetic processes as therapeutic targets. This review highlights an emerging suite of tools that enable robust yet selective interrogation of the epigenome. In addition to allowing site-specific epigenetic editing, these tools can be paired with optogenetic approaches to provide temporal control over epigenetic processes, allowing unparalleled insight into the function of these mechanisms. This improved control promises to revolutionize our understanding of epigenetic modifications in human health and disease states.

Show MeSH
Related in: MedlinePlus