Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory

Nature. 2017 Jun 15;546(7658):381-386. doi: 10.1038/nature22405. Epub 2017 May 31.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetate-CoA Ligase / deficiency
  • Acetate-CoA Ligase / genetics
  • Acetate-CoA Ligase / metabolism*
  • Acetyl Coenzyme A / metabolism
  • Acetylation
  • Animals
  • Cell Differentiation
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Chromatin / enzymology
  • Chromatin / genetics
  • Chromatin / metabolism
  • Gene Expression Regulation, Enzymologic
  • Hippocampus / enzymology*
  • Hippocampus / metabolism
  • Hippocampus / physiology*
  • Histones / chemistry
  • Histones / metabolism*
  • Memory / physiology*
  • Memory Consolidation / physiology
  • Mice
  • Neuronal Plasticity / genetics*
  • Neuronal Plasticity / physiology
  • Neurons / cytology
  • Neurons / metabolism
  • Transcriptional Activation*
  • Up-Regulation


  • Chromatin
  • Histones
  • Acetyl Coenzyme A
  • ACSS2 protein, mouse
  • Acetate-CoA Ligase