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Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory

Nature volume 546, pages 381386 (15 June 2017) | Download Citation


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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  1. 1.

    , & The molecular and systems biology of memory. Cell. 157, 163–186 (2014)

  2. 2.

    , & Epigenetic regulation of memory formation and maintenance. Learn. Mem. 20, 61–74 (2013)

  3. 3.

    & Histone acetylation: molecular mnemonics on the chromatin. Nat. Rev. Neurosci. 14, 97–111 (2013)

  4. 4.

    et al. Transgenic mice expressing a truncated form of CREB-binding protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage. Learn. Mem. 12, 111–119 (2005)

  5. 5.

    , & CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron. 42, 961–972 (2004)

  6. 6.

    & Influence of metabolism on epigenetics and disease. Cell. 153, 56–69 (2013)

  7. 7.

    , & Connecting threads: epigenetics and metabolism. Cell. 148, 24–28 (2012)

  8. 8.

    , , & Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes. Mol. Cell. 42, 426–437 (2011)

  9. 9.

    et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science. 324, 1076–1080 (2009)

  10. 10.

    & The nexus of chromatin regulation and intermediary metabolism. Nature. 502, 489–498 (2013)

  11. 11.

    , , , & Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 21, 805–821 (2015)

  12. 12.

    et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 445, 168–176 (2007)

  13. 13.

    , , & Characterization of a CNS cell line, CAD, in which morphological differentiation is initiated by serum deprivation. J. Neurosci. 17, 1217–1225 (1997)

  14. 14.

    et al. Acetate dependence of tumors. Cell. 159, 1591–1602 (2014)

  15. 15.

    , , , & Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain. Cell. 127, 185–197 (2006)

  16. 16.

    et al. Altered histone acetylation is associated with age-dependent memory impairment in mice. Science. 328, 753–756 (2010)

  17. 17.

    et al. Histone modifiers, YY1 and p300, regulate the expression of cartilage-specific gene, chondromodulin-I, in mesenchymal stem cells. J. Biol. Chem. 285, 29842–29850 (2010)

  18. 18.

    et al. Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J. Neurosci. 27, 6128–6140 (2007)

  19. 19.

    et al. Hippocampal focal knockout of CBP affects specific histone modifications, long-term potentiation, and long-term memory. Neuropsychopharmacology. 36, 1545–1556 (2011)

  20. 20.

    , , , & Dynamic histone marks in the hippocampus and cortex facilitate memory consolidation. Nat. Commun. 3, 991 (2012)

  21. 21.

    et al. Nuclear-cytoplasmic localization of acetyl coenzyme a synthetase-1 in the rat brain. J. Comp. Neurol. 518, 2952–2977 (2010)

  22. 22.

    & The hippocampus and contextual memory retrieval in Pavlovian conditioning. Behav. Brain Res. 110, 97–108 (2000)

  23. 23.

    The Open Field Test: reinventing the wheel. J. Psychopharmacol. 21, 134–135 (2007)

  24. 24.

    et al. The consolidation of object and context recognition memory involve different regions of the temporal lobe. Learn. Mem. 15, 618–624 (2008)

  25. 25.

    , & Effects of ventral and dorsal CA1 subregional lesions on trace fear conditioning. Neurobiol. Learn. Mem. 86, 72–81 (2006)

  26. 26.

    et al. Memory acquisition and retrieval impact different epigenetic processes that regulate gene expression. BMC Genomics. 16, S5 (2015)

  27. 27.

    et al. Brain region-specific gene expression activation required for reconsolidation and extinction of contextual fear memory. J. Neurosci. 29, 402–413 (2009)

  28. 28.

    et al. Object-location training elicits an overlapping but temporally distinct transcriptional profile from contextual fear conditioning. Neurobiol. Learn. Mem. 116, 90–95 (2014)

  29. 29.

    et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell. 159, 1603–1614 (2014)

  30. 30.

    et al. Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. Nat. Commun. 7, 11960 (2016)

  31. 31.

    et al. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol. Cell. 53, 710–725 (2014)

  32. 32.

    , , & Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription. Mol. Cell. 23, 207–217 (2006)

  33. 33.

    , , & Regulation of chromatin states by drugs of abuse. Curr. Opin. Neurobiol. 30, 112–121 (2015)

  34. 34.

    et al. Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev. 27, 1787–1799 (2013)

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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.

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Author notes

    • Ted Abel

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


  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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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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Extended data

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    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.

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