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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

Precision epigenetic reorganization strategies allow interrogation of the specific function of epigenetic modifications in the native cellular context. (A) Editing DNA methylation profiles at a target gene. Hypomethylated genes could be targeted for site-specific methylation using custom gene targeting tools to direct DNA methyltransferases (DNMTs) directly to DNA. Conversely, methylated gene sites could be targeted for conversion to hydroxymethylcytosine (hmC) by directing Tet1, a methylcytosine hydroxylase, directly to DNA. Finally, thymine DNA glycosylases (TDG) could be targeted to hydroxymethylated regions to reintroduce unmethylated cytosines to DNA. (B) Sequence-specific histone editing. DNA is condensed onto histone proteins, which undergo post-translational modification on protruding “tails” (including acetylation of lysine residues) to alter transcriptional capacity. Transcriptional-activator like effector (TALE)-directed recruitment of histone acetyltransferases (such as Creb binding protein, or CBP) directly to a gene site would result in histone acetylation and active transcription. Conversely, targeting of histone deacetylases (such as HDAC2) to a gene site would result in removal of acetyl groups and subsequent gene repression. Thus, epigenetic targeting strategies can serve as bidirectional actuators of transcriptional activity.
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DialoguesClinNeurosci-16-345-g002: Precision epigenetic reorganization strategies allow interrogation of the specific function of epigenetic modifications in the native cellular context. (A) Editing DNA methylation profiles at a target gene. Hypomethylated genes could be targeted for site-specific methylation using custom gene targeting tools to direct DNA methyltransferases (DNMTs) directly to DNA. Conversely, methylated gene sites could be targeted for conversion to hydroxymethylcytosine (hmC) by directing Tet1, a methylcytosine hydroxylase, directly to DNA. Finally, thymine DNA glycosylases (TDG) could be targeted to hydroxymethylated regions to reintroduce unmethylated cytosines to DNA. (B) Sequence-specific histone editing. DNA is condensed onto histone proteins, which undergo post-translational modification on protruding “tails” (including acetylation of lysine residues) to alter transcriptional capacity. Transcriptional-activator like effector (TALE)-directed recruitment of histone acetyltransferases (such as Creb binding protein, or CBP) directly to a gene site would result in histone acetylation and active transcription. Conversely, targeting of histone deacetylases (such as HDAC2) to a gene site would result in removal of acetyl groups and subsequent gene repression. Thus, epigenetic targeting strategies can serve as bidirectional actuators of transcriptional activity.

Mentions: As these studies indicate, it is clear that both methylation and demethylation of specific DNA sequences can be accomplished with these engineered approaches. Indeed, it would seem possible to modulate almost any aspect of DNA methylation status using this general template Figure 2. with the only limitations being the ability to accurately monitor the potential changes in question, and the ability to choose the correct location to modulate transcriptional activity. However, both of these limitations have been diminished by overlapping advances in whole-genome sequencing tools that have been developed to track DNA methylation status in a comprehensive and relatively unbiased fashion.17,71-73 Future studies should employ these sequencing tools to select the most robust and effective strategies for manipulation of epigenetic material. For example, the promoter regions of active genes tend to be demethylated, meaning that tools directing demethylation machinery to these sites would be ineffective, whereas direction of DNMTs to these endogenous loci would likely repress transcription and reduce gene expression.


New approaches to manipulating the epigenome.

Day JJ - Dialogues Clin Neurosci (2014)

Precision epigenetic reorganization strategies allow interrogation of the specific function of epigenetic modifications in the native cellular context. (A) Editing DNA methylation profiles at a target gene. Hypomethylated genes could be targeted for site-specific methylation using custom gene targeting tools to direct DNA methyltransferases (DNMTs) directly to DNA. Conversely, methylated gene sites could be targeted for conversion to hydroxymethylcytosine (hmC) by directing Tet1, a methylcytosine hydroxylase, directly to DNA. Finally, thymine DNA glycosylases (TDG) could be targeted to hydroxymethylated regions to reintroduce unmethylated cytosines to DNA. (B) Sequence-specific histone editing. DNA is condensed onto histone proteins, which undergo post-translational modification on protruding “tails” (including acetylation of lysine residues) to alter transcriptional capacity. Transcriptional-activator like effector (TALE)-directed recruitment of histone acetyltransferases (such as Creb binding protein, or CBP) directly to a gene site would result in histone acetylation and active transcription. Conversely, targeting of histone deacetylases (such as HDAC2) to a gene site would result in removal of acetyl groups and subsequent gene repression. Thus, epigenetic targeting strategies can serve as bidirectional actuators of transcriptional activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

DialoguesClinNeurosci-16-345-g002: Precision epigenetic reorganization strategies allow interrogation of the specific function of epigenetic modifications in the native cellular context. (A) Editing DNA methylation profiles at a target gene. Hypomethylated genes could be targeted for site-specific methylation using custom gene targeting tools to direct DNA methyltransferases (DNMTs) directly to DNA. Conversely, methylated gene sites could be targeted for conversion to hydroxymethylcytosine (hmC) by directing Tet1, a methylcytosine hydroxylase, directly to DNA. Finally, thymine DNA glycosylases (TDG) could be targeted to hydroxymethylated regions to reintroduce unmethylated cytosines to DNA. (B) Sequence-specific histone editing. DNA is condensed onto histone proteins, which undergo post-translational modification on protruding “tails” (including acetylation of lysine residues) to alter transcriptional capacity. Transcriptional-activator like effector (TALE)-directed recruitment of histone acetyltransferases (such as Creb binding protein, or CBP) directly to a gene site would result in histone acetylation and active transcription. Conversely, targeting of histone deacetylases (such as HDAC2) to a gene site would result in removal of acetyl groups and subsequent gene repression. Thus, epigenetic targeting strategies can serve as bidirectional actuators of transcriptional activity.
Mentions: As these studies indicate, it is clear that both methylation and demethylation of specific DNA sequences can be accomplished with these engineered approaches. Indeed, it would seem possible to modulate almost any aspect of DNA methylation status using this general template Figure 2. with the only limitations being the ability to accurately monitor the potential changes in question, and the ability to choose the correct location to modulate transcriptional activity. However, both of these limitations have been diminished by overlapping advances in whole-genome sequencing tools that have been developed to track DNA methylation status in a comprehensive and relatively unbiased fashion.17,71-73 Future studies should employ these sequencing tools to select the most robust and effective strategies for manipulation of epigenetic material. For example, the promoter regions of active genes tend to be demethylated, meaning that tools directing demethylation machinery to these sites would be ineffective, whereas direction of DNMTs to these endogenous loci would likely repress transcription and reduce gene expression.

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