Abstract
Previous reports on epigenetic mechanisms involved in alcohol abuse have focus on hepatic and neuronal regions, leaving the immune system and specifically monocyte-derived dendritic cells (MDDCs) understudied. Our lab has previously shown histone deacetylases are modulated in cells derived from alcohol users and after in vitro acute alcohol treatment of human MDDCs. In the current study, we developed a novel screening tool using matrix assisted laser desorption ionization-fourier transform-ion cyclotron resonance mass spectrometry (MALDI-FT-ICR MS) and single cell imaging flow cytometry to detect post-translational modifications (PTMs) in human MDDCs due to chronic alcohol exposure. Our results demonstrate, for the first time, in vitro chronic alcohol exposure of MDDCs modulates H3 and H4 and induces a significant increase in acetylation at H4K12 (H4K12ac). Moreover, the Tip60/HAT inhibitor, NU9056, was able to block EtOH-induced H4K12ac, enhancing the effect of EtOH on IL-15, RANTES, TGF-β1, and TNF-α cytokines while restoring MCP-2 levels, suggesting that H4K12ac may be playing a major role during inflammation and may serve as an inflammation regulator or a cellular stress response mechanism under chronic alcohol conditions.
Highlights
The notion that an epigenetic modification can be described as a heritable change in genetic composition that is not directly encoded in the DNA1 has fascinated researchers over time
In order to study the functional relevance of upregulation of H4K12ac due to chronic alcohol exposure in monocyte-derived dendritic cells (MDDCs), we looked at secretion of inflammatory cytokine and chemokine profiles under the treatment of NU9056 alone, chronic EtOH treatment, and combination of chronic EtOH and NU9056
In the current study nucleosome density was not measured, the detected increase in H3 and H4 may not be a direct correlation towards increase in nucleosome density and this effect may be induced by cell stress due to chronic EtOH treatment as previously shown during extra-nuclear detection of histones and nucleosomes in activated human lymphoblasts as an early event in apoptosis[22]
Summary
The notion that an epigenetic modification can be described as a heritable change in genetic composition that is not directly encoded in the DNA1 has fascinated researchers over time. In the context of addiction, epigenetic modifications have been implicated in alcohol abuse[2,3,4,5]. Researchers have begun to investigate the epigenetic effects of alcohol abuse; most studies have been conducted in the hepatic[2] or neuronal regions[7,8] as recently reviewed by us[9]. The current study aims to reveal the epigenetic effects of chronic alcohol treatment in monocyte-derived dendritic cells (MDDCs), the ability of chronic alcohol to induce histone modifications and subsequent functional effects. Results from this study provide novel insights into the epigenetic effects of chronic www.nature.com/scientificreports/. Alcohol in the periphery and reveal H4K12ac as a novel epigenetic post-translational modification marker for chronic alcohol
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