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Nestler epigenetic

Ming-Hu Han, Eric J Nestler
There is an urgent need for more effective medications to treat major depressive disorder, as fewer than half of depressed patients achieve full remission and many are not responsive with currently available antidepressant medications or psychotherapy. It is known that prolonged stressful events are an important risk factor for major depressive disorder. However, there are prominent individual variations in response to stress: a relatively small proportion of people (10-20%) experiencing prolonged stress develop stress-related psychiatric disorders, including depression (susceptibility to stress), whereas most stress-exposed individuals maintain normal psychological functioning (resilience to stress)...
April 10, 2017: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
Linlin Sun, Jian-Yuan Zhao, Xiyao Gu, Lingli Liang, Shaogen Wu, Kai Mo, Jian Feng, Weixiang Guo, Jun Zhang, Alex Bekker, Xinyu Zhao, Eric J Nestler, Yuan-Xiang Tao
Opioids are the gold standard for pharmacological treatment of neuropathic pain, but their analgesic effects are unsatisfactory in part due to nerve injury-induced downregulation of opioid receptors in dorsal root ganglia (DRG) neurons. How nerve injury drives such downregulation remains elusive. DNA methyltransferase (DNMT)-triggered DNA methylation represses gene expression. We show here that blocking the nerve injury-induced increase in DRG DNMT3a (a de novo DNMT) rescued the expression of Oprm1 and Oprk1 mRNAs and their respective encoding mu-opioid receptor (MOR) and kappa-opioid receptor (KOR) proteins in the injured DRG...
March 4, 2017: Pain
Jian Feng, Catherine J Pena, Immanuel Purushothaman, Olivia Engmann, Deena Walker, Amber N Brown, Orna Issler, Marie Doyle, Eileen Harrigan, Ezekiell Mouzon, Vincent Vialou, Li Shen, Meelad M Dawlaty, Rudolf Jaenisch, Eric J Nestler
Depression is a leading cause of disease burden, yet current therapies fully treat <50% of affected individuals. Increasing evidence implicates epigenetic mechanisms in depression and antidepressant action. Here we examined a possible role for the DNA dioxygenase, ten-eleven translocation protein 1 (TET1), in depression-related behavioral abnormalities. We applied chronic social defeat stress, an ethologically validated mouse model of depression-like behaviors, and examined Tet1 expression changes in nucleus accumbens (NAc), a key brain reward region...
January 25, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Georgia E Hodes, Deena M Walker, Benoit Labonté, Eric J Nestler, Scott J Russo
Epigenetics refers to potentially heritable processes that can mediate both lasting and transient changes in gene expression in the absence of genome sequence alterations. The field of epigenetics has introduced a novel understanding of the mechanisms through which the environment can shape an individual and potentially its offspring. This Mini-Review examines the current literature exploring the role of epigenetics in the development of mood disorders such as depression. Depression is twofold more common in females, yet the majority of preclinical research has been conducted exclusively in male subjects...
January 2, 2017: Journal of Neuroscience Research
Diane M Damez-Werno, HaoSheng Sun, Kimberly N Scobie, Ningyi Shao, Jaclyn Rabkin, Caroline Dias, Erin S Calipari, Ian Maze, Catherine J Pena, Deena M Walker, Michael E Cahill, Ramesh Chandra, Amy Gancarz, Ezekiell Mouzon, Joseph A Landry, Hannah Cates, Mary-Kay Lobo, David Dietz, C David Allis, Ernesto Guccione, Gustavo Turecki, Paola Defilippi, Rachael L Neve, Yasmin L Hurd, Li Shen, Eric J Nestler
Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms-such as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans...
August 23, 2016: Proceedings of the National Academy of Sciences of the United States of America
Tianyuan Wang, Janine H Santos, Jian Feng, David C Fargo, Li Shen, Gonzalo Riadi, Elizabeth Keeley, Zachary S Rosh, Eric J Nestler, Richard P Woychik
Repetitive elements (REs) comprise 40-60% of the mammalian genome and have been shown to epigenetically influence the expression of genes through the formation of fusion transcript (FTs). We previously showed that an intracisternal A particle forms an FT with the agouti gene in mice, causing obesity/type 2 diabetes. To determine the frequency of FTs genome-wide, we developed a TopHat-Fusion-based analytical pipeline to identify FTs with high specificity. We applied it to an RNA-seq dataset from the nucleus accumbens (NAc) of mice repeatedly exposed to cocaine...
2016: PloS One
Elizabeth A Heller, Peter J Hamilton, Dominika D Burek, Sonia I Lombroso, Catherine J Peña, Rachael L Neve, Eric J Nestler
UNLABELLED: Recent studies have implicated epigenetic remodeling in brain reward regions following psychostimulant or stress exposure. It has only recently become possible to target a given type of epigenetic remodeling to a single gene of interest, and to probe the functional relevance of such regulation to neuropsychiatric disease. We sought to examine the role of histone modifications at the murine Cdk5 (cyclin-dependent kinase 5) locus, given growing evidence of Cdk5 expression in nucleus accumbens (NAc) influencing reward-related behaviors...
April 27, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Eric J Nestler
There has been increasing interest in the possibility that behavioral experience--in particular, exposure to stress--can be passed on to subsequent generations through heritable epigenetic modifications. The possibility remains highly controversial, however, reflecting the lack of standardized definitions of epigenetics and the limited empirical support for potential mechanisms of transgenerational epigenetic inheritance. Nonetheless, growing evidence supports a role for epigenetic regulation as a key mechanism underlying lifelong regulation of gene expression that mediates stress vulnerability...
March 2016: PLoS Biology
Eric J Nestler, Catherine J Peña, Marija Kundakovic, Amanda Mitchell, Schahram Akbarian
Psychiatric disorders are complex multifactorial illnesses involving chronic alterations in neural circuit structure and function as well as likely abnormalities in glial cells. While genetic factors are important in the etiology of most mental disorders, the relatively high rates of discordance among identical twins, particularly for depression and other stress-related syndromes, clearly indicate the importance of additional mechanisms. Environmental factors such as stress are known to play a role in the onset of these illnesses...
October 2016: Neuroscientist: a Review Journal Bringing Neurobiology, Neurology and Psychiatry
HaoSheng Sun, Diane M Damez-Werno, Kimberly N Scobie, Ning-Yi Shao, Caroline Dias, Jacqui Rabkin, Ja Wook Koo, Erica Korb, Rosemary C Bagot, Francisca H Ahn, Michael E Cahill, Benoit Labonté, Ezekiell Mouzon, Elizabeth A Heller, Hannah Cates, Sam A Golden, Kelly Gleason, Scott J Russo, Simon Andrews, Rachael Neve, Pamela J Kennedy, Ian Maze, David M Dietz, C David Allis, Gustavo Turecki, Patrick Varga-Weisz, Carol Tamminga, Li Shen, Eric J Nestler
Improved treatment for major depressive disorder (MDD) remains elusive because of the limited understanding of its underlying biological mechanisms. It is likely that stress-induced maladaptive transcriptional regulation in limbic neural circuits contributes to the development of MDD, possibly through epigenetic factors that regulate chromatin structure. We establish that persistent upregulation of the ACF (ATP-utilizing chromatin assembly and remodeling factor) ATP-dependent chromatin-remodeling complex, occurring in the nucleus accumbens of stress-susceptible mice and depressed humans, is necessary for stress-induced depressive-like behaviors...
October 2015: Nature Medicine
Katherine N Wright, Fiona Hollis, Florian Duclot, Amanda M Dossat, Caroline E Strong, T Chase Francis, Roger Mercer, Jian Feng, David M Dietz, Mary Kay Lobo, Eric J Nestler, Mohamed Kabbaj
Epigenetic mechanisms, such as histone modifications, regulate responsiveness to drugs of abuse, such as cocaine, but relatively little is known about the regulation of addictive-like behaviors by DNA methylation. To investigate the influence of DNA methylation on the locomotor-activating effects of cocaine and on drug-seeking behavior, rats receiving methyl supplementation via chronic l-methionine (MET) underwent either a sensitization regimen of intermittent cocaine injections or intravenous self-administration of cocaine, followed by cue-induced and drug-primed reinstatement...
June 10, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Xuan Li, F Javier Rubio, Tamara Zeric, Jennifer M Bossert, Sarita Kambhampati, Hannah M Cates, Pamela J Kennedy, Qing-Rong Liu, Raffaello Cimbro, Bruce T Hope, Eric J Nestler, Yavin Shaham
Cue-induced methamphetamine seeking progressively increases after withdrawal (incubation of methamphetamine craving), but the underlying mechanisms are largely unknown. We determined whether this incubation is associated with alterations in candidate genes in dorsal striatum (DS), a brain area implicated in cue- and context-induced drug relapse. We first measured mRNA expression of 24 candidate genes in whole DS extracts after short (2 d) or prolonged (1 month) withdrawal in rats following extended-access methamphetamine or saline (control condition) self-administration (9 h/d, 10 d)...
May 27, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Renaud Massart, Royi Barnea, Yahav Dikshtein, Matthew Suderman, Oren Meir, Michael Hallett, Pamela Kennedy, Eric J Nestler, Moshe Szyf, Gal Yadid
One of the major challenges of cocaine addiction is the high rate of relapse to drug use after periods of withdrawal. During the first few weeks of withdrawal, cue-induced cocaine craving intensifies, or "incubates," and persists over extended periods of time. Although several brain regions and molecular mechanisms were found to be involved in this process, the underlying epigenetic mechanisms are still unknown. Herein, we used a rat model of incubation of cocaine craving, in which rats were trained to self-administer cocaine (0...
May 27, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Jian Feng, Ningyi Shao, Keith E Szulwach, Vincent Vialou, Jimmy Huynh, Chun Zhong, Thuc Le, Deveroux Ferguson, Michael E Cahill, Yujing Li, Ja Wook Koo, Efrain Ribeiro, Benoit Labonte, Benjamin M Laitman, David Estey, Victoria Stockman, Pamela Kennedy, Thomas Couroussé, Isaac Mensah, Gustavo Turecki, Kym F Faull, Guo-li Ming, Hongjun Song, Guoping Fan, Patrizia Casaccia, Li Shen, Peng Jin, Eric J Nestler
Ten-eleven translocation (TET) enzymes mediate the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is enriched in brain, and its ultimate DNA demethylation. However, the influence of TET and 5hmC on gene transcription in brain remains elusive. We found that ten-eleven translocation protein 1 (TET1) was downregulated in mouse nucleus accumbens (NAc), a key brain reward structure, by repeated cocaine administration, which enhanced behavioral responses to cocaine. We then identified 5hmC induction in putative enhancers and coding regions of genes that have pivotal roles in drug addiction...
April 2015: Nature Neuroscience
Giannina Descalzi, Daigo Ikegami, Toshikazu Ushijima, Eric J Nestler, Venetia Zachariou, Minoru Narita
Neuropathic and inflammatory pain promote a large number of persisting adaptations at the cellular and molecular level, allowing even transient tissue or nerve damage to elicit changes in cells that contribute to the development of chronic pain and associated symptoms. There is evidence that injury-induced changes in chromatin structure drive stable changes in gene expression and neural function, which may cause several symptoms, including allodynia, hyperalgesia, anxiety, and depression. Recent findings on epigenetic changes in the spinal cord and brain during chronic pain may guide fundamental advances in new treatments...
April 2015: Trends in Neurosciences
Ja Wook Koo, Michelle S Mazei-Robison, Quincey LaPlant, Gabor Egervari, Kevin M Braunscheidel, Danielle N Adank, Deveroux Ferguson, Jian Feng, Haosheng Sun, Kimberly N Scobie, Diane M Damez-Werno, Efrain Ribeiro, Catherine Jensen Peña, Deena Walker, Rosemary C Bagot, Michael E Cahill, Sarah Ann R Anderson, Benoit Labonté, Georgia E Hodes, Heidi Browne, Benjamin Chadwick, Alfred J Robison, Vincent F Vialou, Caroline Dias, Zachary Lorsch, Ezekiell Mouzon, Mary Kay Lobo, David M Dietz, Scott J Russo, Rachael L Neve, Yasmin L Hurd, Eric J Nestler
Brain-derived neurotrophic factor (BDNF) has a crucial role in modulating neural and behavioral plasticity to drugs of abuse. We found a persistent downregulation of exon-specific Bdnf expression in the ventral tegmental area (VTA) in response to chronic opiate exposure, which was mediated by specific epigenetic modifications at the corresponding Bdnf gene promoters. Exposure to chronic morphine increased stalling of RNA polymerase II at these Bdnf promoters in VTA and altered permissive and repressive histone modifications and occupancy of their regulatory proteins at the specific promoters...
March 2015: Nature Neuroscience
Deena M Walker, Hannah M Cates, Elizabeth A Heller, Eric J Nestler
Drug addiction involves long-term behavioral abnormalities and gene expression changes throughout the mesolimbic dopamine system. Epigenetic mechanisms establish/maintain alterations in gene expression in the brain, providing the impetus for investigations characterizing how epigenetic processes mediate the effects of drugs of abuse. This review focuses on evidence that epigenetic events, specifically histone modifications, regulate gene expression changes throughout the reward circuitry. Drugs of abuse induce changes in histone modifications throughout the reward circuitry by altering histone-modifying enzymes, manipulation of which reveals a role for histone modification in addiction-related behaviors...
February 2015: Current Opinion in Neurobiology
Rosemary C Bagot, Benoit Labonté, Catherine J Peña, Eric J Nestler
Psychiatric disorders are complex multifactorial disorders involving chronic alterations in neural circuit structure and function. While genetic factors play a role in the etiology of disorders such as depression, addiction, and schizophrenia, relatively high rates of discordance among identical twins clearly point to the importance of additional factors. Environmental factors, such as stress, play a major role in the psychiatric disorders by inducing stable changes in gene expression, neural circuit function, and ultimately behavior...
September 2014: Dialogues in Clinical Neuroscience
Elizabeth A Heller, Hannah M Cates, Catherine J Peña, Haosheng Sun, Ningyi Shao, Jian Feng, Sam A Golden, James P Herman, Jessica J Walsh, Michelle Mazei-Robison, Deveroux Ferguson, Scott Knight, Mark A Gerber, Christian Nievera, Ming-Hu Han, Scott J Russo, Carol S Tamminga, Rachael L Neve, Li Shen, H Steve Zhang, Feng Zhang, Eric J Nestler
Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. We investigated the mechanism linking chromatin dynamics to neurobiological phenomena by applying engineered transcription factors to selectively modify chromatin at a specific mouse gene in vivo...
December 2014: Nature Neuroscience
Jian Feng, Matthew Wilkinson, Xiaochuan Liu, Immanuel Purushothaman, Deveroux Ferguson, Vincent Vialou, Ian Maze, Ningyi Shao, Pamela Kennedy, JaWook Koo, Caroline Dias, Benjamin Laitman, Victoria Stockman, Quincey LaPlant, Michael E Cahill, Eric J Nestler, Li Shen
BACKGROUND: Increasing evidence supports a role for altered gene expression in mediating the lasting effects of cocaine on the brain, and recent work has demonstrated the involvement of chromatin modifications in these alterations. However, all such studies to date have been restricted by their reliance on microarray technologies that have intrinsic limitations. RESULTS: We use next generation sequencing methods, RNA-seq and ChIP-seq for RNA polymerase II and several histone methylation marks, to obtain a more complete view of cocaine-induced changes in gene expression and associated adaptations in numerous modes of chromatin regulation in the mouse nucleus accumbens, a key brain reward region...
April 22, 2014: Genome Biology
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