Nucleosome Repositioning: A Novel Mechanism for Nicotine- and Cocaine-Induced Epigenetic Changes

Amber N Brown,Cynthia Vied,Pradeep G Bhide,Jonathan H Dennis,Shu-Ichi Okamoto

doi:10.1371/journal.pone.0139103

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.

Highlights

Drugs of abuse cause dramatic changes in the brain, often leading to risky and compulsive drug-seeking behavior characterized as addiction
Undifferentiated SH-SY5Y cells used in our studies express α and β subunits of nicotinic acetylcholine receptors, D1- and D2-like dopamine (DA) receptors, the dopamine transporter (DAT), tyrosine hydroxylase (TH)[17], and exhibit ERK1/2 signaling following nicotine treatment [18]
We recognize that the undifferentiated SH-SY5Y cells do not fully represent the complexities of heterogeneous neuronal populations in the intact brain because mature neurons can exhibit shorter linker DNA compared to other cell types [25, 26]

Summary

Introduction

Drugs of abuse cause dramatic changes in the brain, often leading to risky and compulsive drug-seeking behavior characterized as addiction. Underlying these behavioral alterations are brain-region and cell-type specific changes in gene expression, mediated in part by epigenetic modifications to DNA and/or histone proteins, as well as local changes in chromatin compaction. Changes in DNA methylation and histone modifications have been reported in brain regions associated with the reward circuitry following exposure to drugs of abuse, such as PLOS ONE | DOI:10.1371/journal.pone.0139103. Nucleosome repositioning may be one such mechanism [5], whether it plays a role in modifying DNA accessibility following exposure to drugs of abuse has not been addressed until now

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Conclusion