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Cited by 227Neurotransmitter Receptor Influence on BehaviorEpigenetics and DNA MethylationGenomics and Chromatin Dynamics

Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors

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Heller, Elizabeth A, Cates, Hannah M, Peña, Catherine J, Sun, Haosheng, Shao, Ningyi, Feng, Jian, Golden, Sam A, Herman, James P +14 more·2014·Nature Neuroscience
DOI 10.1038/nn.3871PMC PMC4241193
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Abstract

Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. We investigated the mechanism linking chromatin dynamics to neurobiological phenomena by applying engineered transcription factors to selectively modify chromatin at a specific mouse gene in vivo. We found that histone methylation or acetylation at the Fosb locus in nucleus accumbens, a brain reward region, was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery. This approach allowed us to relate the epigenetic landscape at a given gene directly to regulation of its expression and to its subsequent effects on reward behavior.

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  • The true causality of epigenetic signatures at DNA sites that are known to be involved in stress-related disorders can only be examined with the advent of novel mutagenesis tools such as CRISPR-Cas9 and TALENs.

    “For example, the true causality of epigenetic signatures at DNA sites that are known to be involved in stress-related disorders can only be examined with the advent of novel mutagenesis tools such as Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR-Cas9) and Transcription Activator-Like Effector Nucleases (TALENs).425,426”

    From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [425]

    The Introduction describes testing the causal role of stress-evoked epigenetic regulation with engineered zinc-finger proteins (ZFPs) and transcription activator-like effectors (TALEs). The Discussion reports that ZFP-induced modification at FosB produced depression-related behaviors in mice. This contradicts the claim that causality can only be examined with CRISPR-Cas9 and TALENs; the paper describes TALE-based transcription factors, not TALEN mutagenesis. Our copy provides section labels but no page numbers. (LLM, conf=0.87)

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Authors
Heller, E. A., Cates, H. M., Peña, C. J., Sun, H., Shao, N., Feng, J., Golden, S. A., Herman, J. P., Walsh, J. J., Mazei-Robison, M., Ferguson, D., Knight, S., Gerber, M. A., Nievera, C., Han, M.-H., Russo, S. J., Tamminga, C. S., Neve, R. L., Shen, L., Zhang, H. S., Zhang, F., & Nestler, E. J.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • National Institutes of Health (US)
  • McGovern Institute for Brain Research (US)
  • Sigma-Aldrich (United States) (US)
  • Massachusetts Institute of Technology (US)
  • Sangamo BioSciences (United States) (US)
Corresponding author
Nestler, Eric J
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2014-10-27
Volume
17
Issue
12
Pages
1720-1727
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.3871
PMC
PMC4241193
OpenAlex
W1976125136
Cited by
227
References
7
Citations by year
2026: 6 · 2025: 16 · 2024: 17 · 2023: 9 · 2022: 15 · 2021: 15 · 2020: 14 · 2019: 20 · 2018: 29 · 2017: 28 · 2016: 35 · 2015: 22 · 2014: 1
FWCI
13.11
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Alcohol Abuse and Alcoholism (R01AA022445)
  • National Institute of Mental Health (P50MH096890, R00MH094405)
  • National Institute on Drug Abuse (T32DA007135, R37DA007359, F32DA035518, P01DA008227)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • 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 remodeling, histone methylation, histone acetylation, FosB, nucleus accumbens, drug addiction, stress, reward behavior, transcriptional regulation
MeSH terms
Adult, Animals, Depression, Female, Humans, Male, Mice, Inbred C57BL, Middle Aged, Nucleus Accumbens, Behavior, Addictive, Proto-Oncogene Proteins c-fos, Epigenesis, Genetic, Cell Line, Tumor, Mice, Genetic Loci

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