Journal article
Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory
Nature (London), Vol.546(7658), pp.381-386
06/15/2017
DOI: 10.1038/nature22405
PMCID: PMC5505514
PMID: 28562591
Abstract
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.
Details
- Title: Subtitle
- Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory
- Creators
- Philipp Mews - Epigenetics Institute, Departments of Cell and Developmental Biology, Biology, Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USAGreg Donahue - Epigenetics Institute, Departments of Cell and Developmental Biology, Biology, Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USAAdam M Drake - Epigenetics Institute, Departments of Cell and Developmental Biology, Biology, Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USAVincent Luczak - Epigenetics Institute, Departments of Cell and Developmental Biology, Biology, Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USATed Abel - Epigenetics Institute, Departments of Cell and Developmental Biology, Biology, Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USAShelley L Berger - Epigenetics Institute, Departments of Cell and Developmental Biology, Biology, Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.546(7658), pp.381-386
- DOI
- 10.1038/nature22405
- PMID
- 28562591
- PMCID
- PMC5505514
- NLM abbreviation
- Nature
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Publisher
- Springer Science and Business Media LLC; England
- Grant note
- P01 AG031862 / NIA NIH HHS R01 MH087463 / NIMH NIH HHS
- Language
- English
- Date published
- 06/15/2017
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9984065738302771
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