Vol 11, N°3 Neurotoxicity and Neuroprotection
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amily history is one of the greatest risk factors for psychiatric disorders, yet their genetic basis remains poorly understood despite substantial advances in whole genome sequencing techniques. While the search for genetic mutations continues at a rapid pace, the field is also investigating the environmental component of fam- ily history, which has remained more difficult to explain mechanistically. One hypothesis is that environmental stimuli alter gene expression patterns in certain brain regions that ultimately change neural function and behavior. Support for this hypothesis has been observed in animal models of psychiatric illness, as well as in human patients. The interactions between the environment and the genes that give rise to specific phenotypes are termed “epige- netic.”1 An example of this process is observed in cellu- lar differentiation, where unique chemical signals induce totipotent stem cells to differentiate into genetically identical cell types with vastly different functions. This is due in part to the vastly different sets of genes expressed between distinct cell types (eg, neurons vs hepatocytes), despite their identical DNA templates. Mechanistic insight into this process has recently been uncovered, and involves the transduction of unique environmental signals into precise and highly stable alterations in chro- matin structure that ultimately gate access of transcrip- tional machinery to specific gene programs, thereby pro- viding unique gene expression profiles in response to specific environmental cues.2 Importantly, many of these chromatin remodeling mechanisms are highly stable, contributing to the maintenance of specific gene expres- sion programs in the correct tissues throughout the life of an individual. The strong control exerted by chromatin remodeling on gene expression, and the potential stability of chromatin T r a n s l a t i o n a l  r e s e a r c h F Copyright © 2009 LLS SAS. All rights reserved www.dialogues-cns.org Chromatin regulation in drug addiction and depression William Renthal, PhD; Eric J. Nestler, MD, PhD  Keywords:  chromatin remodeling; histone acetylation; histone methylation; DNA methylation; BDNF; glucocorticoid receptor; cocaine; stress Author affiliations: Medical Scientist Training Program, The University of Texas Southwestern Medical Center, Dallas, Texas, USA (William Renthal); Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA (Eric J. Nestler) Address for correspondence: Eric J. Nestler, Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA (e-mail: eric.nestler@mssm.edu) Alterations in gene expression are implicated in the pathogenesis of several neuropsychiatric disorders, including drug addiction and depression. Increasing evi- dence indicates that changes in gene expression in neu- rons, in the context of animal models of addiction and depression, are mediated in part by epigenetic mecha- nisms that alter chromatin structure on specific gene pro- moters. This review discusses recent findings from behav- ioral, molecular, and bioinformatic approaches that are being used to understand the complex epigenetic regu- lation of gene expression in brain by drugs of abuse and by stress. These advances promise to open up new avenues for improved treatments of these disorders. © 2009, LLS SAS Dialogues Clin Neurosci. 2009;11:257-268.