title: Regulation of DNA methylation by ethanol induces tissue plasminogen activator expression in astrocytes.
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.
authors.affiliation: Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA; Jesse Brown VA Medical Center, Chicago, Illinois, USA.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Zhang
authors.forename: Handojo
authors.initials: H
authors.lastname: Kusumo
authors.forename: Amul J
authors.initials: AJ
authors.lastname: Sakharkar
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Pandey
authors.forename: Marina
authors.initials: M
authors.lastname: Guizzetti
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D000077209:Decitabine; D004797:Enzyme-Linked Immunosorbent Assay; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D011247:Pregnancy; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis*
chemical_list: D000964:Antimetabolites, Antineoplastic; D002492:Central Nervous System Depressants; D012333:RNA, Messenger; D000431:Ethanol; D012313:RNA; D000077209:Decitabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D010959:Tissue Plasminogen Activator; D001374:Azacitidine
keywords: DNA methylation; DNA methyltransferase; astrocytes; ethanol; tissue plasminogen activator