Alcohol metabolism contributes to brain histone acetylation

Area of Science:

• Neuroscience
• Epigenetics
• Metabolism

Background:

• Epigenetic regulation, including histone acetylation, is influenced by metabolic state.
• Acetyl-CoA, crucial for histone acetylation in neurons, is produced from acetate by acetyl-CoA synthetase 2 (ACSS2).
• Alcohol metabolism significantly increases blood acetate levels, suggesting a link between alcohol consumption and neuronal epigenetic modifications.

Purpose of the Study:

• To investigate whether alcohol metabolism directly influences histone acetylation in the brain.
• To determine the role of acetyl-CoA synthetase 2 (ACSS2) in alcohol-induced epigenetic changes.
• To explore the impact of alcohol-derived acetate on neuronal gene expression and behavior.

Main Methods:

• In vivo stable-isotope labeling in mice to trace acetyl group origins.
• Administration of labeled alcohol and acetate to assess incorporation into brain histones.
• Ex vivo experiments with primary hippocampal neurons to study transcriptional responses.
• In vivo assessment of alcohol-related associative learning in the presence and absence of ACSS2 activity.

Main Results:

• Alcohol metabolism was shown to cause rapid histone acetylation in the brain.
• Direct deposition of alcohol-derived acetyl groups onto histones, dependent on ACSS2, was observed.
• Labeled acetate and alcohol exposure led to acetyl group incorporation in fetal brains.
• Extracellular acetate induced learning and memory-related transcriptional programs in neurons, sensitive to ACSS2 inhibition.
• Alcohol-related associative learning was found to require ACSS2.

Conclusions:

• Alcohol metabolism directly contributes to histone acetylation in the brain via an ACSS2-dependent pathway.
• This mechanism links alcohol consumption to gene regulation in the brain, affecting neuronal function and behavior.
• The findings highlight a direct metabolic link between alcohol, epigenetic modifications, and cognitive processes like learning and memory.