Regulation of DNA methylation by ethanol induces tissue plasminogen activator expression in astrocytes

Authors

  • Xiaolu Zhang,

    1. Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA
    2. Jesse Brown VA Medical Center, Chicago, Illinois, USA
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    • These authors contributed equally to this work.
  • Handojo Kusumo,

    1. Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA
    2. Jesse Brown VA Medical Center, Chicago, Illinois, USA
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    • These authors contributed equally to this work.
  • Amul J. Sakharkar,

    1. Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA
    2. Jesse Brown VA Medical Center, Chicago, Illinois, USA
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  • Subhash C. Pandey,

    1. Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA
    2. Jesse Brown VA Medical Center, Chicago, Illinois, USA
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  • Marina Guizzetti

    Corresponding author
    1. Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA
    2. Jesse Brown VA Medical Center, Chicago, Illinois, USA
    3. Department of Environmental and Health Sciences, University of Washington, Seattle, Washington, USA
    • Address correspondence and reprint requests to Marina Guizzetti, Jesse Brown VA Medical Center, Research and Development Section (M/C 151), 820 South Damen Avenue, Chicago, IL 60612, USA. E-mail: mguizzetti@psych.uic.edu

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Abstract

Alcohol exposure affects neuronal plasticity in the adult and developing brain. Astrocytes play a major role in modulating neuronal plasticity and are a target of ethanol. Tissue plasminogen activator (tPA) is involved in modulating neuronal plasticity by degrading the extracellular matrix proteins including fibronectin and laminin and is up-regulated by ethanol in vivo. In this study we explored the hypothesis that ethanol affects DNA methylation in astrocytes thereby increasing expression and release of tPA. It was found that ethanol increased tPA mRNA levels, an effect mimicked by an inhibitor of DNA methyltransferase (DNMT) activity. Ethanol also increased tPA protein expression and release, and inhibited DNMT activity with a corresponding decrease in DNA methylation levels of the tPA promoter. Furthermore, it was observed that protein levels of DNMT3A, but not DNMT1, were reduced in astrocytes after ethanol exposure. These novel studies show that ethanol inhibits DNA methylation in astrocytes leading to increased tPA expression and release; this effect may be involved in astrocyte-mediated inhibition of neuronal plasticity by alcohol.

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We propose that ethanol, by decreasing DNMT-3a (DNA methyltransferase) levels and by inhibiting DNMT activity, reduces DNA methylation of the tissue plasminogen activator (tPA) promoter and leads to increased tPA mRNA and protein expression in astrocytes; tPA released is also increased by ethanol. As tPA promotes the degradation of neuritogenic extracellular matrix, the observed dysregulation of the epigenetic mechanism of DNA methylation in astyrocytes may be involved in ethanol-induced inhibition of astrocyte-mediated neuritogenesis.

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