# Regulation of Gene Enhancers in Human Heroin Use

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $266,961

## Abstract

PROJECT SUMMARY/ABSTRACT– PROJECT 4
 Project 4’s objective is to characterize the influence of enhancer regions of the genome, which exert
crucial control over gene expression, in opiate addiction. Work in several tissues has demonstrated that
enhancer regions are “marked” by several specific histone modifications, such as H3K27ac (histone 3 Lys27
acetylation), and are enriched in several chromatin remodeling factors. One example is BRD4, a member of
the BET (bromodomain and extra-terminal) subfamily, which binds acetylated histones through its
bromodomains and is tightly linked with enhancers in several tissues. We have found elevated tissue levels of
both H3K27ac and BRD4 in striatum of humans with heroin use disorders, with such elevations correlating
strongly with years of heroin use and expression levels of key gene networks. Similar regulation is seen in
striatum of rats that self-administer heroin. Moreover, we have found that small molecules that disrupt
BRD4/BET function—in clinical development for cancer treatment—exert therapeutic-like effects in heroin
addiction models in rodents. This Project will further these studies in several ways. We will obtain genome-
wide maps of enhancer regions in NAc and DS of humans with heroin use disorders and matched controls,
and in rats after heroin self-administration, by use of ChIP-seq for H3K27ac and BRD4, among other marks, in
conjunction with the Gene and Chromatin Analysis Core. This will be performed separately on nuclei isolated
from neurons and non-neuronal cells of these brain regions. We will work with the Core on advanced
bioinformatics approaches to overlay these datasets, which is required for reliable identification of enhancers,
along with RNA-seq and ATAC-seq datasets that we are currently generating on the same samples and that
will provide further insight into the specific target genes affected by the identified heroin-regulated enhancers.
We will test the causal role of enhancer regulation in heroin addiction by studying the effect of bidirectional
manipulations of BRD4 in NAc and DS on gene expression and behavioral endpoints in rat models, including
screening several BRD4/BET inhibitors for anti-addiction actions. These studies offer a translational
opportunity to advance novel therapies for drug addiction.

## Key facts

- **NIH application ID:** 9864078
- **Project number:** 5P01DA047233-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** YASMIN L. HURD
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $266,961
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864078

## Citation

> US National Institutes of Health, RePORTER application 9864078, Regulation of Gene Enhancers in Human Heroin Use (5P01DA047233-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9864078. Licensed CC0.

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