# Impact of Chronic Alcohol Consumption on the Functional and Epigenetic Landscapes of Monocytes and Their Progenitors

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $19,832

## Abstract

Project Summary:
Alcohol consumption is widespread in the United States with ~7% of alcohol-consuming individuals engaging in
heavy alcohol use. It is well established that chronic heavy drinking (CHD) is associated with increased
susceptibility to infections as well as impaired wound healing and tissue repair resulting in poor post-operative
outcomes. Evidence suggests that many of these defects are mediated by excessive inflammatory responses
originating from myeloid cells, notably circulating monocytes and tissue-resident macrophages. However, many
of the current studies rely on in vitro exposure of monocytes from healthy donors or cell lines to high doses of
ethanol. Due to a lack of studies utilizing reliable in vivo models, our understanding of the mechanisms underlying
aberrant inflammatory responses in the context of CHD remains incomplete. In order to address these knowledge
gaps, we propose to leverage a rhesus macaque model of voluntary ethanol self-administration that accurately
mirrors human physiology and recapitulates complex human drinking behavior. Using this model, our lab has
recently demonstrated that CHD results in transcriptional and epigenetic rewiring of circulating monocytes and
splenic macrophages, resulting in aberrant responses to LPS stimulation. However, the functional implications
of and the epigenetic mechanisms controlling this reprogramming remain unknown. Importantly, because
monocytes are short-lived circulating cells under constant repopulation from the bone marrow, these
observations suggest perturbations of the hematopoietic niche. Preliminary single-cell analyses of hematopoietic
progenitors point to a shift in differentiation potential towards more mature myeloid progenitors with alcohol.
However, a link between this phenotype in progenitor cells and their differentiated states in blood remains
unclear. In this application, we propose to test the hypothesis that chronic alcohol consumption reprograms
the epigenetic landscape of monocyte progenitors in the bone marrow giving rise to circulating
monocytes poised towards a hyper-inflammatory response. We will first examine the impact of CHD on
functional reprogramming of circulating monocytes, implementing assays to test their ability to migrate,
phagocytose, and generate proper metabolic responses. We will then examine the effect of stimulation on the
monocyte epigenetic landscape through assessment of chromatin accessibility and differential binding of histone
modifications with alcohol. Finally, we will determine the effect of CHD on the differentiation potential,
transcriptome activation, and epigenetic rewiring of bone marrow myeloid progenitors. We will perform functional
assays on monocytes derived in vitro from granulocyte/monocyte progenitors and integrate these data with those
obtained from peripheral monocytes. Further, scRNA-Seq analysis and epigenetic assessment of the myeloid
progenitors will allow us to determine the specific effects of alcohol...

## Key facts

- **NIH application ID:** 10252788
- **Project number:** 5F31AA028704-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Sloan Alexandra Lewis
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $19,832
- **Award type:** 5
- **Project period:** 2020-09-01 → 2021-12-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10252788

## Citation

> US National Institutes of Health, RePORTER application 10252788, Impact of Chronic Alcohol Consumption on the Functional and Epigenetic Landscapes of Monocytes and Their Progenitors (5F31AA028704-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10252788. Licensed CC0.

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