# X chromosome inactivation in sex disparities to substance use disorder

> **NIH NIH DP1** · OHIO STATE UNIVERSITY · 2024 · $84,500

## Abstract

PROJECT SUMMARY/ABSTRACT
There is a sex-based disparity associated with substance abuse disorders, which is evidenced by preclinical and
clinical studies. Females are generally more vulnerable to the initiation, escalation and withdrawal effects of
substance abuse behavior than males. Although these differences have largely been attributed to hormonal
differences, evidence for non-hormonal factors that regulate addiction has been demonstrated by a number of
studies. However, the mechanisms underlying sex chromosome influences on substance abuse behavior
represent a huge gap in our knowledge base on the epigenetics of substance use disorders. We propose a novel
hypothesis that escape from X-chromosome inactivation (XCI) in females contributes to sex associated
differences in addiction behavior. We will apply cutting edge technology and uniquely novel approaches and
tools we developed recently to comprehensively investigate the impact of XCI escape on sex associated
disparities in addiction. XCI is an epigenetic mechanism that occurs in mammalian females and serves to
equalize gene expression between the sexes. Females have two X chromosomes (XX), and during XCI, one X
chromosome is randomly chosen to be transcriptionally silenced. However, it is known that a number of X linked
genes escape XCI and display bi allelic gene expression. The objective of this proposal is to determine the
contribution of XCI escape on sex-associated differences in substance abuse disorder. First, we will use novel
cutting edge mouse models to characterize cellular mono-allelic (XCI) or bi-allelic (XCI escape) gene expression
of specific X-linked genes associated with addiction to opioids and psychostimulants: monoamine oxidase A
(Maoa) and GABAA receptor A3 (Gabra3). I pioneered an innovative approach using a gene specific dual bi-
cistronic reporter mouse as a tool to enable the visualization of allelic usage of these addiction associated genes
in vivo in a model of addiction. Next, we will determine the molecular landscape of XCI in brain tissue and specific
neuronal cells during chronic exposure to opioids and psychostimulants, using a highly innovative single cell
RNA sequencing technology. To accomplish these goals, I have assembled a talented, multidisciplinary team of
research collaborators in addiction, neuroscience, genetic mouse modelling, bioinformatics and biostatistics.
This innovative approach to the study and analysis of gene specific XCI escape as an epigenetic mechanism in
the context of substance abuse has the potential to open up a new area of research on the epigenetics of
addiction. Further, these genetically modified mice can be used to study XCI escape as an epigenetic mechanism
in other neurologic disorders. As an early stage investigator, these studies will also advance my long term
objective of becoming a future leader in the epigenetics of substance use disorders.

## Key facts

- **NIH application ID:** 11075595
- **Project number:** 3DP1DA054344-03S1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Steve Onyeka Oghumu
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $84,500
- **Award type:** 3
- **Project period:** 2021-08-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11075595

## Citation

> US National Institutes of Health, RePORTER application 11075595, X chromosome inactivation in sex disparities to substance use disorder (3DP1DA054344-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11075595. Licensed CC0.

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