title: Nucleosome Repositioning: A Novel Mechanism for Nicotine- and Cocaine-Induced Epigenetic Changes.
abstract: Drugs of abuse modify behavior by altering gene expression in the brain. Gene expression can be regulated by changes in DNA methylation as well as by histone modifications, which alter chromatin structure, DNA compaction and DNA accessibility. In order to better understand the molecular mechanisms directing drug-induced changes in chromatin structure, we examined DNA-nucleosome interactions within promoter regions of 858 genes in human neuroblastoma cells (SH-SY5Y) exposed to nicotine or cocaine. Widespread, drug- and time-resolved repositioning of nucleosomes was identified at the transcription start site and promoter region of multiple genes. Nicotine and cocaine produced unique and shared changes in terms of the numbers and types of genes affected, as well as repositioning of nucleosomes at sites which could increase or decrease the probability of gene expression based on DNA accessibility. Half of the drug-induced nucleosome positions approximated a theoretical model of nucleosome occupancy based on physical and chemical characteristics of the DNA sequence, whereas the basal or drug naïve positions were generally DNA sequence independent. Thus we suggest that nucleosome repositioning represents an initial dynamic genome-wide alteration of the transcriptional landscape preceding more selective downstream transcriptional reprogramming, which ultimately characterizes the cell- and tissue-specific responses to drugs of abuse.
authors.affiliation: Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, United States of America.
authors.forename: Amber N
authors.initials: AN
authors.lastname: Brown
authors.affiliation: Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, United States of America.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Vied
authors.affiliation: Department of Biological Sciences, Florida State University, Tallahassee, Florida, United States of America.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Dennis
authors.affiliation: Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, United States of America.
authors.forename: Pradeep G
authors.initials: PG
authors.lastname: Bhide
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D003042:Cocaine / Q000494:pharmacology*; D051766:Early Growth Response Protein 1 / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D063990:Gene Ontology; D006801:Humans; D009538:Nicotine / Q000494:pharmacology*; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D009707:Nucleosomes; D009538:Nicotine; D003042:Cocaine