Article

Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory

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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.

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Gene Expression Omnibus

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Acknowledgements

We thank the NeuronsRUs core of the Mahoney Institute for Neurological Sciences for preparations of primary hippocampal neurons. T.A. is supported by RO1 MH 087463. P.M. and S.L.B. are supported by NIH P01AG031862.

Author information

Author notes

    • Ted Abel

    Present address: Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.

Affiliations

  1. Epigenetics Institute, Departments of Cell and Developmental Biology, Biology, Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA

    • Philipp Mews
    • , Greg Donahue
    • , Adam M. Drake
    • , Vincent Luczak
    • , Ted Abel
    •  & Shelley L. Berger

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Contributions

P.M. and S.L.B. conceived the project. P.M. performed most of the experiments. A.M.D. analysed the CAD RNA-seq datasets. P.M. and G.D. performed and analysed CAD ACSS2i and hippocampal RNA-seq experiments. A.M.D. and G.D. analysed ChIP–seq datasets. P.M. and V.L. performed in vivo ACSS2 knockdown and behavioural characterization. P.M. and S.L.B. wrote the manuscript. All authors reviewed the manuscript and discussed the work.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Shelley L. Berger.

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Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    This file was replaced on 7 June 2017 to remove a duplicate page. Shown are the original western blots with size marker indications. Outlined in red are the cropped blot data presented in Figures 1c, 1e, 2g, 2h, 2j, 4b and Extended Data Figures 1b and 6b.

Text files

  1. 1.

    Supplementary Table 1

    A list of genes upregulated 1.6-fold or higher upon CAD neuronal differentiation, corresponding to the top 10% of upregulated genes by fold-change. NextSeq mRNA sequencing data were aligned by RNA-STAR 2.3.0.e to the mm10 reference genome, and mapped to genomic features using cufflinks-2.2.1 and mm10 UCSC genomic transcript loci. The rRNA, mRNA, and tRNA of the mouse genome were downloaded from the goldenPath UCSC FTP and were masked from the transcriptome analysis.