# Epigenetic-metabolic aspects of alcohol use disorder and early developmental alcohol exposure

> **NIH NIH K99** · UNIVERSITY OF PENNSYLVANIA · 2021 · $145,400

## Abstract

PROJECT SUMMARY/ABSTRACT
Alcohol use disorder (AUD) continues to impose a tremendous burden on society and efficacious treatment
options are severely lacking. Recently, epigenetic processes such as histone acetylation emerged as potential
contributors to AUD. Acetylation of histones has been shown to facilitate DNA accessibility and gene expression.
The dynamic and reversible nature of this process makes it a particularly promising potential therapeutic target.
 Novel evidence suggests that epigenetic regulation is dependent on metabolic state, implicating specific
metabolic factors in neural functions that drive behavior (Li*, Egervari* et al, Nat Rev Mol Cell Biol 2018).
Recently, our group has shown that neuronal histone acetylation is fueled by the metabolite acetyl-CoA that is
produced from acetate by nuclear Acetyl-CoA Synthetase 2 (ACSS2; Mews et al, Nature 2017). As a major
biological source of acetate is alcohol metabolism, I hypothesized that alcohol-derived acetate might have
profound effects on the epigenetic landscape in the brain following binge drinking. Using heavy isotope labeling
in mice, I showed that alcohol metabolism rapidly promotes histone acetylation in the brain by direct deposition
of alcohol-derived acetyl groups onto histones in an ACSS2-dependent manner. I observed similar incorporation
of alcohol-derived acetate into fetal brain, suggesting a potential role for ACSS2 during prenatal alcohol
exposure. In adult mice, alcohol-induced histone acetylation led to increased expression of key neuronal genes
linked to learning and memory. Strikingly, ACSS2 was required for ethanol-induced associative learning, which
underlies craving and relapse after protracted periods of abstinence (Mews*, Egervari*# et al, Nature, 2019).
These preliminary findings establish a direct and dynamic link between peripheral and central alcohol metabolism
and brain histone acetylation with significant therapeutic potential.
 In this proposal, I will aim to (1) determine the importance of ACSS2 in voluntary alcohol intake and test
whether ACSS2 inhibition decreases alcohol consumption in mice; (2) characterize the role of ACSS2 in prenatal
alcohol exposure and in the development of fetal alcohol spectrum disorder; and (3) explore the potential
relevance of this novel pathway in various brain regions that regulate different aspects of AUD. This study will
make pioneering contributions to our understanding of alcohol’s effects on the brain with respect to epigenetic
and metabolic processes, and has the potential to identify new pharmaceutical targets to ameliorate alcohol use
disorder. In addition, the proposed training and research will greatly facilitate my transition to an independent
tenured-track faculty position. I will learn a combination of computational, genomic and proteomic techniques
and behavioral approaches that will help establish my niche and provide me with the skills necessary to work at
the intersection of epigenetics, metabolism...

## Key facts

- **NIH application ID:** 10156033
- **Project number:** 1K99AA028577-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Gabor Egervari
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $145,400
- **Award type:** 1
- **Project period:** 2021-01-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10156033

## Citation

> US National Institutes of Health, RePORTER application 10156033, Epigenetic-metabolic aspects of alcohol use disorder and early developmental alcohol exposure (1K99AA028577-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10156033. Licensed CC0.

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