Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory
Open accessAbstract
Metabolic production of acetyl coenzyme A (acetyl-CoA) is linked to histone acetylation and gene regulation, but the precise mechanisms of this process are largely unknown. Here we show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) directly regulates histone acetylation in neurons and spatial memory in mammals. In a neuronal cell culture model, ACSS2 increases in the nuclei of differentiating neurons and localizes to upregulated neuronal genes near sites of elevated histone acetylation. A decrease in ACSS2 lowers nuclear acetyl-CoA levels, histone acetylation, and responsive expression of the cohort of neuronal genes. In adult mice, attenuation of hippocampal ACSS2 expression impairs long-term spatial memory, a cognitive process that relies on histone acetylation. A decrease in ACSS2 in the hippocampus also leads to defective upregulation of memory-related neuronal genes that are pre-bound by ACSS2. These results reveal a connection between cellular metabolism, gene regulation, and neural plasticity and establish a link between acetyl-CoA generation 'on-site' at chromatin for histone acetylation and the transcription of key neuronal genes.
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Recent studies provide evidence for metabolic signaling to chromatin in the brain.
“Recent studies provide evidence for metabolic signaling to chromatin in the brain.419”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [419]
Acetyl coenzyme A synthetase in the hippocampus of mice is necessary for epigenetic regulation of transcription of genes involved in neuroplasticity dynamics and memory formation.
“A very new study showed that acetyl coenzyme A synthetase in the hippocampus of mice is necessary for epigenetic regulation of transcription of genes involved in neuroplasticity dynamics and memory formation.156”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [156]
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- Authors
- Mews, P., Donahue, G., Drake, A. M., Luczak, V., Abel, T., & Berger, S. L.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Berger, Shelley L.
- Venue
- Nature
- Published
- 2017-05-31
- Volume
- 546
- Issue
- 7658
- Pages
- 381-386
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5505514
- OpenAlex
- W2619419337
- Cited by
- 514
- References
- 34
- Citations by year
- 2026: 60 · 2025: 64 · 2024: 81 · 2023: 55 · 2022: 56 · 2021: 49 · 2020: 42 · 2019: 50 · 2018: 39 · 2017: 17
- FWCI
- 23.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (R01AA027202)
- National Institute on Aging (P01AG031862)
- National Institute of Mental Health (R01MH087463)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- acetyl-CoA synthetase 2, histone acetylation, hippocampal-dependent memory, spatial memory, chromatin, acetate metabolism, neuroplasticity, long-term memory consolidation, metabolic regulation of gene expression
- MeSH terms
- Memory Consolidation, Acetyl Coenzyme A, Acetate-CoA Ligase, Acetylation, Animals, Cell Differentiation, Cell Nucleus, Cells, Cultured, Chromatin, Hippocampus, Histones, Memory, Neuronal Plasticity, Neurons, Transcriptional Activation, Up-Regulation, Gene Expression Regulation, Enzymologic, Mice
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