Cited by 76CRISPR and Genetic EngineeringEpigenetics and DNA MethylationGenomics and Chromatin Dynamics

In vivo locus-specific editing of the neuroepigenome

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Yim, Yun Young, Teague, Collin D., Nestler, Eric J.·2020·Nature Reviews Neuroscience

Abstract

Studies over the past several decades have identified numerous epigenetic mechanisms associated with pathological states in psychiatric and neurological disease. Until recently, studies investigating chromatin-regulatory proteins, using overexpression or knockdown approaches, did not establish causal roles for epigenetic modifications at specific genes because these techniques typically affect hundreds or thousands of genomic loci. In this Review, we describe recent efforts in using locus-specific neuroepigenome editing in vivo to, for the first time, define causal relationships between a single chromatin modification at a specific gene in a defined cell population and downstream measures at the molecular, cellular, circuit and behavioural levels. We briefly introduce three epigenome-editing platforms: zinc-finger proteins, transcriptional activator-like effectors and clustered regularly interspaced short palindromic repeats (CRISPR). We then explore the development of in vivo neuroepigenome-editing tools and their applications to resolve epigenetic contributions to the pathophysiology of brain diseases. We also discuss technical considerations for in vivo neuroepigenome-editing experiments and ongoing innovations in the field, including new tools to investigate chromatin marks, manipulate chromatin topology and induce epigenetic modifications at multiple genes in the same cell. Lastly, we explore the potential clinical applications of in vivo neuroepigenome editing for treating brain pathology.

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  • Cell-type-specific expression of epigenetic modifiers (e.g., histone acetylation or methylation proteins) fused to dCas9 can be made inducible by Cre recombinase, which can be transgenically or virally co-expressed.

    “The cell-type-specific expression of epigenetic modifiers (e.g., histone acetylation or methylation proteins) fused to dCas9 are then inducible by Cre recombinase, which can be transgenically or virally co-expressed [155, 156].”
  • Determining whether epigenetic modifications at select loci are causal mechanisms of behavior may only be possible by altering target epigenetic modifications in vivo.

    “Interpretational challenges also extend to determining whether epigenetic modifications at select loci are ‘causal’ mechanisms of behavior, which may only be possible by altering target epigenetic modifications in vivo [155–157].”
  • Tools used for cell-type-specific epigenetic editing include zinc-finger proteins, which can be fused with histone modifiers and target specific DNA sequences, and transcriptional activator-like effectors (TALEs), DNA binding proteins from bacteria that can be targeted to regulate gene transcription.

    “Tools used for cell-type-specific epigenetic editing include zinc-finger proteins, which can be fused with histone modifiers and target specific DNA sequences, and transcriptional activator-like effectors (TALEs), DNA binding proteins from bacteria that can be targeted to regulate gene transcription (see review [156]).”

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Authors
Yim, Y. Y., Teague, C. D., & Nestler, E. J.
Affiliations
Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Nestler, Eric J.
Venue
Nature Reviews Neuroscience
Published
2020-07-23
Volume
21
Issue
9
Pages
471-484
ISSN
  • 1471-003X (ISSN-L)
  • 1471-0048
OpenAlex
W3044612680
Cited by
76
References
110
Citations by year
2026: 8 · 2025: 9 · 2024: 11 · 2023: 9 · 2022: 19 · 2021: 16 · 2020: 4
FWCI
1.15
Type
journal article
Language
en
Open access
Locations
  • Nature reviews. Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (R01MH051399)
  • National Institute on Drug Abuse (P01DA047233, R01DA007359)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
chromatin modification, zinc finger proteins, CRISPR, chromatin topology
MeSH terms
Gene Editing, Animals, Brain Diseases, Chromatin, Humans, Epigenesis, Genetic, Epigenomics

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