# Targeting the host metabolome to reverse drug-induced epigenetic changes

> **NIH NIH DP1** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $508,500

## Abstract

Project Summary
Pathological substance use disorders are a set of devastating psychiatric conditions marked by a pattern of
escalating and out of control drug intake and an often-persistent cycle of withdrawal and relapse. One of the
critical questions for translational research on substance use disorders is how exposure to drugs of abuse
leads to such persistent dysregulation in patterns of motivated behaviors. Long-lasting changes to chromatin
structure underlie the persistent dysregulation of gene expression and behavior seen in substance use
disorders. Regulation of chromatin structure requires the integration of a myriad of signals from the
environment, and there is a robust literature demonstrating that levels of key metabolites and cofactors
regulate chromatin dynamics. Notably, nearly all enzymes that modify histones or DNA utilize key metabolites
as substrates or cofactors in their catalytic activity. Therefore, availability of key metabolites directly affects the
ability of a cell to make alter chromatin structure. Our preliminary studies show that repeated exposure to drugs
of abuse markedly alters the serum and brain metabolome. Many of the dysregulated metabolites are those
known to be critical cofactors for the function of epigenetic writers and erasers. Parallel to this, genes involved
in the regulation of cellular metabolism in the nucleus accumbens were markedly altered even after prolonged
withdrawal. Taken together, these data identify the metabolome as a novel means to target epigenetic
regulation in substance use disorders. Initial studies will utilize drug self-administration and reinstatement
coupled with serum and brain metabolomics to further identify metabolites that correlate with drug intake and
drug seeking. Subsequent studies will determine how manipulations of metabolite signaling alter behavioral
response and brain epigenetics. Systemic manipulation of metabolites via dietary restriction or
supplementation will clarify the role of these metabolites on behavior, and cell-specific gene manipulations of
key metabolic enzymes will add specificity and clarity to observed effects. Metabolic manipulations will be
coupled with cell-specific chromatin profiling via ATAC-sequencing, quantitative mass spectrometry to identify
changes in histone modifications, and chromatin-associated protein complexes in order to examine the
interaction of behavioral and epigenetic effects. Finally, we will utilize cutting edge transgenic mouse
technology to create inducible point mutations in epigenetic writers/erasers at key metabolite binding sites to
assess the effects on behavior and chromatin structure when enzyme-metabolite interactions are prevented.
These studies will define a new field of research targeting metabolic regulation of chromatin in substance use
disorders and will identify novel translational research targets that will markedly increase our understanding of
epigenetic regulation in substance use disorders.

## Key facts

- **NIH application ID:** 10205016
- **Project number:** 5DP1DA051551-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Drew Kiraly
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $508,500
- **Award type:** 5
- **Project period:** 2020-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10205016

## Citation

> US National Institutes of Health, RePORTER application 10205016, Targeting the host metabolome to reverse drug-induced epigenetic changes (5DP1DA051551-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10205016. Licensed CC0.

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