Epigenetic Mechanisms Regulating the Functional Effects of Chronic Alcohol Exposure of Human Monocyte-derived Dendritic Cells

Authors

Tiyash Parira, florida International UniversityFollow

Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Biomedical Sciences

First Advisor's Name

Marisela Agudelo, Ph.D.

First Advisor's Committee Title

Committee Chair

Second Advisor's Name

Madhavan Nair, Ph.D.

Second Advisor's Committee Title

committee member

Third Advisor's Name

Hoshang Unwalla, Ph.D.

Third Advisor's Committee Title

Committee member

Fourth Advisor's Name

Manuel Barbieri, Ph.D.

Fourth Advisor's Committee Title

committee member

Fifth Advisor's Name

Sabita Roy, Ph.D.

Fifth Advisor's Committee Title

committee member

Keywords

Alcohol Use Disorders, Epigenetics, Immunology

Date of Defense

11-6-2018

Abstract

The effects of alcohol abuse are multi-dimensional since alcohol is widely known to affect both the innate and adaptive immune systems. Recently, epigenetics has come into focus and has been implicated in many diseases as well as substance abuse disorders. Therefore, research efforts of understanding the epigenetic mechanisms underlying substance abuse effects including alcohol abuse have become more predominant.

In our laboratory, we have studied different epigenetic changes induced by alcohol exposure including regulation of histone deacetylases (HDACs), histone quantity, and histone modifications such as acetylation and deacetylation. We have observed differential effects of acute and chronic alcohol exposure in human monocyte-derived dendritic cells (MDDCs) wherein our laboratory previously found that HDACs were modulated in MDDCs treated acutely with alcohol in vitro, and in MDDCs from alcohol users. Our previous work has also demonstrated that alcohol consumption affects the dendritic cell function by modulating inflammatory markers and cannabinoid receptors such as CB₂ and GPR55 through epigenetic modifications. For instance, chronic alcohol exposure upregulates histone (H) 4 acetylation at lysine 12 (H4k12ac) and acute alcohol effects on histone acetylation are associated with an increase in GPR55 expression.

The hypothesis of the study is that chronic alcohol modulates human MDDC function through epigenetic mechanisms. Therefore, the primary objective of this research project is to elucidate novel pathways involving histone post-translational modifications due to chronic alcohol exposure in human dendritic cells.

For this study, monocytes isolated from commercially available human buffy coats were differentiated into MDDCs, which were treated with chronic alcohol levels of 0.1 % (100mg/dL) and 0.2 % (200mg/dL) for 5 days in the presence or absence of the histone acetyltransferase inhibitor NU9056 (50nM) or the GPR55 antagonist CID16020046 (5µM). Results showed that chronic alcohol levels upregulated H4K12ac in MDDCs and this was associated with a concomitant increase in GPR55 gene and protein expression. Further, NU9056 and CID16020046 were able to reduce alcohol-induced inflammatory chemokine MCP-2 and reactive oxygen species production indicating that H4K12ac may be an inflammation and oxidative stress regulator. Additionally, NU9056 and CID16020046 could potentially reduce alcohol-induced inflammation and serve as potential therapeutic targets for alcohol use disorders.

Identifier

FIDC007017

ORCID

https://orcid.org/0000-0003-4503-1997

Comments

Parts of this Dissertation has been published in Scientific Reports and Journal of Alcoholism and Drug Dependence. The author is first author in the published papers.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Recommended Citation

Parira, Tiyash, "Epigenetic Mechanisms Regulating the Functional Effects of Chronic Alcohol Exposure of Human Monocyte-derived Dendritic Cells" (2018). FIU Electronic Theses and Dissertations. 3890.
https://digitalcommons.fiu.edu/etd/3890