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Examining the metabolic-epigenetic regulation of alcohol intake and associated molecular mechanisms

Award Number: R01AA033369
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/13/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Examining the metabolic-epigenetic regulation of alcohol intake and associated molecular mechanisms - ABSTRACT Alcohol use disorder (AUD) continues to impose a tremendous burden on society and efficacious treatment options are severely lacking. Recently, epigenetic mechanisms such as increased histone acetylation emerged as potential contributors to AUD. The dynamic and reversible nature of these processes makes them particularly promising potential therapeutic targets. Novel evidence suggests that epigenetic regulation is dependent on metabolic state (Li*, Egervari* et al, Nat Rev Mol Cell Biol 2018 or Egervari et al, Science 2020). Recently, we have shown that acetate generated during alcohol metabolism has profound effects on brain histone acetylation. Using heavy isotope labeling in mice, we found that alcohol-derived acetate is rapidly deposited on histones in the brain, and that this pathway is mediated by Acetyl-CoA Synthetase 2 (ACSS2), a nuclear metabolic enzyme that converts acetate into acetyl- CoA. We showed that alcohol-induced histone acetylation leads to increased expression of key neuronal genes linked to learning and memory and, importantly, that this pathway is required for ethanol-induced associative learning, which underlies craving and relapse after protracted periods of abstinence (Mews*, Egervari*# et al, Nature 2019). In addition, we found that mice not expressing ACSS2 consume significantly less alcohol in models of voluntary alcohol intake (Egervari et al, Neuropharmacology 2025). Our pioneering findings establish a direct and dynamic link between alcohol metabolism and brain histone acetylation with significant therapeutic potential. Importantly, however, the specific mechanisms by which alcohol-derived acetate impacts the brain and behavior remain largely unknown. Here we propose to use a unique blend of cutting edge genomic, proteomic and behavioral approaches to explore mechanistic aspects of behavioral and transcriptional regulation by alcohol-derived acetate in the brain. Specifically, we will test the functional importance of ACSS2 and specific histone proteins (namely histone variant H2A.Z.1) in alcohol-associated learning, consummatory and motivational aspects of alcohol drinking, as well as underlying molecular changes. Further, we will interrogate the mechanisms by which systemic surges of alcohol-derived acetate result in sex- and brain region-specific molecular outcomes. We will investigate the spatial and temporal distribution of alcohol-derived acetate across the male and female mouse brain, assess regional and sex differences in the incorporation of acetate into histone acetylation, and uncover the specific neuronal and non-neuronal cell populations that are sensitive to the gene regulatory effects of alcohol-derived acetate. Overall, results from this proposal will outline key mechanisms by which alcohol-derived acetate impacts the brain and behavior and will also have widespread implications for our general understanding of how metabolites regulate gene expression. Importantly, our results will guide the development of future therapies targeting the metabolic-epigenetic axis for AUD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $555,331 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Alcohol Research Programs	000	1	8/17/2026	NEW	$555,331
														Subtotal = $555,331

Grand Total All Awards = $555,331

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Examining the metabolic-epigenetic regulation of alcohol intake and associated molecular mechanisms

Award Number: R01AA033369

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/13/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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