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Stress-induced epigenetic transcriptional memory of acetylcholinesterase by HDAC4
Open accessAbstract
Stress induces long-lasting changes in neuronal gene expression and cholinergic neurotransmission, but the underlying mechanism(s) are incompletely understood. Here, we report that chromatin structure and histone modifications are causally involved in this transcriptional memory. Specifically, the AChE gene encoding the acetylcholine-hydrolyzing enzyme acetylcholinesterase is known to undergo long-lasting transcriptional and alternative splicing changes after stress. In mice subjected to stress, we identified two alternative 5′ exons that were down-regulated after stress in the hippocampus, accompanied by reduced acetylation and elevated trimethylation of H3K9 at the corresponding promoter. These effects were reversed completely by daily administration of the histone deacetylase (HDAC) inhibitor sodium butyrate for 1 wk after stress. H3K9 hypoacetylation was associated with a selective, sodium butyrate-reversible promoter accumulation of HDAC4. Hippocampal suppression of HDAC4 in vivo completely abolished the long-lasting AChE-related and behavioral stress effects. Our findings demonstrate long-lasting stress-inducible changes in AChE's promoter choices, identify the chromatin changes that support this long-term transcriptional memory, and reveal HDAC4 as a mediator of these effects in the hippocampus.
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“These effects were reversed drastically by administration an HDAC inhibitor, and reduced hippocampal HDAC4 levels restored the long-lasting behavioral deficit.136”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [136]
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“The AChE gene, which encodes the acetylcholine-hydrolyzing enzyme acetylcholinesterase, was downregulated in the hippocampus after stress and accompanied by decreased acetylation and increased trimethylation of H3K9 at the corresponding promoter, as well as HDAC4 accumulation in hippocampal neurons.”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [136]
In the citing paper
“Another study reported increased hippocampal HDAC4 following chronic stress exposure, 84 whereas suppression of hippocampal HDAC4 abolished the long-lasting behavioral deficits induced by stress.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [84]
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Metadata
- Authors
- Sailaja, B. S., Cohen-Carmon, D., Zimmerman, G., Soreq, H., & Meshorer, E.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Departments of aGenetics and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-12-10
- Volume
- 109
- Issue
- 52
- Pages
- E3687-95
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3535662
- OpenAlex
- W2102812580
- Cited by
- 121
- References
- 47
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 10 · 2023: 7 · 2022: 5 · 2021: 10 · 2020: 7 · 2019: 10 · 2018: 5 · 2017: 10 · 2016: 14 · 2015: 14 · 2014: 15 · 2013: 10
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Israel Science Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- acetylcholinesterase, HDAC4, histone deacetylase, stress, transcriptional memory, alternative splicing, H3K9 acetylation, H3K9 trimethylation, histone modifications, chromatin structure, sodium butyrate, hippocampus, cholinergic neurotransmission, long-term stress effects
- MeSH terms
- Acetylcholinesterase, Animals, Chromatin, Exons, Hippocampus, Histone Deacetylases, Male, Neurons, Promoter Regions, Genetic, Stress, Physiological, Swimming, Transcription, Genetic, DNA Methylation, Gene Silencing, Epigenesis, Genetic, Mice, Histone Deacetylase Inhibitors
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