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Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory

Author

Listed:
  • Philipp Mews

    (Epigenetics Institute, Biology, Genetics, University of Pennsylvania Perelman School of Medicine)

  • Greg Donahue

    (Epigenetics Institute, Biology, Genetics, University of Pennsylvania Perelman School of Medicine)

  • Adam M. Drake

    (Epigenetics Institute, Biology, Genetics, University of Pennsylvania Perelman School of Medicine)

  • Vincent Luczak

    (Epigenetics Institute, Biology, Genetics, University of Pennsylvania Perelman School of Medicine)

  • Ted Abel

    (Epigenetics Institute, Biology, Genetics, University of Pennsylvania Perelman School of Medicine
    University of Iowa Carver College of Medicine)

  • Shelley L. Berger

    (Epigenetics Institute, Biology, Genetics, University of Pennsylvania Perelman School of Medicine)

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.

Suggested Citation

  • Philipp Mews & Greg Donahue & Adam M. Drake & Vincent Luczak & Ted Abel & Shelley L. Berger, 2017. "Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory," Nature, Nature, vol. 546(7658), pages 381-386, June.
    • Handle: RePEc:nat:nature:v:546:y:2017:i:7658:d:10.1038_nature22405
    DOI: 10.1038/nature22405
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    Cited by:

    1. Xiaotong Li & Jason Karpac, 2023. "A distinct Acyl-CoA binding protein (ACBP6) shapes tissue plasticity during nutrient adaptation in Drosophila," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Charlotte M. François & Thomas Pihl & Marion Dunoyer de Segonzac & Chloé Hérault & Bruno Hudry, 2023. "Metabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Wen-Xiang Liu & Hai-Ning Liu & Zhan-Ping Weng & Qi Geng & Yue Zhang & Ya-Feng Li & Wei Shen & Yang Zhou & Teng Zhang, 2023. "Maternal vitamin B1 is a determinant for the fate of primordial follicle formation in offspring," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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