title: Ethanol-induced changes in poly (ADP ribose) polymerase and neuronal developmental gene expression.
abstract: Prenatal alcohol exposure has profound effects on neuronal growth and development. Poly-ADP Ribose Polymerase (PARP) enzymes are perhaps unique in the field of epigenetics in that they directly participate in histone modifications, transcription factor modifications, DNA methylation/demethylation and are highly inducible by ethanol. It was our hypothesis that ethanol would induce PARP enzymatic activity leading to alterations in neurodevelopmental gene expression. Mouse E18 cortical neurons were treated with ethanol, PARP inhibitors, and nuclear hormone receptor transcription factor PPARγ agonists and antagonists. Subsequently, we measured PARP activity and changes in Bdnf, OKSM (Oct4, Klf4, Sox2, c-Myc), DNA methylating/demethylating factors, and Pparγ mRNA expression, promoter 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC), and PPARγ promoter binding. We found that ethanol reduced Bdnf4, 9a, and Klf4 mRNA expression, and increased c-Myc expression. These changes were reversed with a PARP inhibitor. In agreement with its role in DNA demethylation PARP inhibition increased 5MC levels at the c-Myc promoter. In addition, we found that inhibition of PARP enzymatic activity increased PPARγ promoter binding, and this corresponded to increased Bdnf and Klf4 mRNA expression. Our results suggest that PARP participates in DNA demethylation and reduces PPARγ promoter binding. The current study underscores the importance of PARP in ethanol-induced changes to neurodevelopmental gene expression.
authors: Jesse Brown Veterans Affairs Medical Center, 820 South Damen Avenue (M/C 151), Chicago, IL 60612, USA; Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612, USA. Electronic address: dgavin@psych.uic.edu.
authors: David P
authors: DP
authors: Gavin
authors: Jesse Brown Veterans Affairs Medical Center, 820 South Damen Avenue (M/C 151), Chicago, IL 60612, USA; Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612, USA.
authors: Handojo
authors: H
authors: Kusumo
authors: Jesse Brown Veterans Affairs Medical Center, 820 South Damen Avenue (M/C 151), Chicago, IL 60612, USA; Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612, USA.
authors: Rajiv P
authors: RP
authors: Sharma
authors: Department of Behavioral Neuroscience, Oregon Health & Science University, 3181 SW Sam Jackson Park Road L470, Portland, OR 97239, USA; VA Portland Health Care System, 3710 SW US Veterans Hospital Rd, Portland, OR 97239, USA.
authors: Marina
authors: M
authors: Guizzetti
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000633:toxicity*; D063647:Fetal Alcohol Spectrum Disorders / Q000201:enzymology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D050437:Genes, Developmental / Q000187:drug effects; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C489428:Myc protein, mouse; D018696:Neuroprotective Agents; D047495:PPAR gamma; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D000431:Ethanol; D011065:Poly(ADP-ribose) Polymerases
keywords: Alcoholism; CpG; Epigenetic; Histone