Acute and chronic alcohol exposure evidently influences epigenetic changes, both transiently and permanently, and these changes in turn influence a variety of cells and organ systems throughout the body. Many of the alcohol-induced epigenetic modifications can contribute to cellular adaptations that ultimately lead to behavioral tolerance and alcohol dependence. The persistence of behavioral changes demonstrates that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. The research activities over the past years have demonstrated a crucial role of epigenetic mechanisms in causing long lasting and transient changes in the expression of several genes in diverse tissues, including brain. This has stimulated recent research work that is aimed at characterizing the influence of epigenetic regulatory events in mediating the long lasting and transient effects of alcohol abuse on the brain in humans and animal models of alcohol addiction. In this study, we update our current understanding of the impact of alcohol exposure on epigenetic mechanisms in the brain and refurbish the knowledge of epigenetics in the direction of new drugs development.

1.
Waddington CH: The Strategy of the Genes, a Discussion of Some Aspects of Theoretical Biology. London, Allen & Unwin, 1957, p 262.
2.
Morgan HD, Sutherland HG, Martin DI, Whitelaw E: Epigenetic inheritance at the agouti locus in the mouse. Nat Genet 1999;23:314-318.
3.
Jaenisch R, Bird A: Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003;33(suppl):245-254.
4.
Zovkic IB, Guzman-Karlsson MC, Sweatt JD: Epigenetic regulation of memory formation and maintenance. Learn Mem 2013;20:61-74.
5.
Trudell JR, Messing RO, Mayfield J, Harris RA: Alcohol dependence: molecular and behavioral evidence. Trends Pharmacol Sci 2014;35:317-323.
6.
Dick DM, Kendler KS: The impact of gene-environment interaction on alcohol use disorders. Alcohol Res 2012;34:318-324.
7.
Contet C, Gardon O, Filliol D, Becker JA, Koob GF, Kieffer BL: Identification of genes regulated in the mouse extended amygdala by excessive ethanol drinking associated with dependence. Addict Biol 2011;16:615-619.
8.
Tabakoff B, Saba L, Printz M, Flodman P, Hodgkinson C, Goldman D, et al: Genetical genomic determinants of alcohol consumption in rats and humans. BMC Biol 2009;7:70.
9.
Botia B, Legastelois R, Alaux-Cantin S, Naassila M: Expression of ethanol-induced behavioral sensitization is associated with alteration of chromatin remodeling in mice. PLoS One 2012;7:e47527.
10.
Ponomarev I, Wang S, Zhang L, Harris RA, Mayfield RD: Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence. J Neurosci 2012;32:1884-1897.
11.
Dulac C: Brain function and chromatin plasticity. Nature 2010;465:728-735.
12.
Jones PA: Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 2012;13:484-492.
13.
Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D'Souza C, Fouse SD, et al: Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 2010;466:253-257.
14.
Wagner JR, Busche S, Ge B, Kwan T, Pastinen T, Blanchette M: The relationship between DNA methylation, genetic and expression inter-individual variation in untransformed human fibroblasts. Genome Biol 2014;15:R37.
15.
Ladd-Acosta C, Pevsner J, Sabunciyan S, Yolken RH, Webster MJ, Dinkins T, et al: DNA methylation signatures within the human brain. Am J Hum Genet 2007;81:1304-1315.
16.
Weber M, Hellmann I, Stadler MB, Ramos L, Pääbo S, Rebhan M, et al: Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 2007;39:457-466.
17.
Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY: Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999;23:185-188.
18.
Chestnut BA, Chang Q, Price A, Lesuisse C, Wong M, Martin LJ: Epigenetic regulation of motor neuron cell death through DNA methylation. J Neurosci 2011;31:16619-16636.
19.
Nardone S, Sams DS, Reuveni E, Getselter D, Oron O, Karpuj M, et al: DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways. Transl Psychiatry 2014;4:e433.
20.
Coppieters N, Dieriks BV, Lill C, Faull RL, Curtis MA, Dragunow M: Global changes in DNA methylation and hydroxymethylation in Alzheimer's disease human brain. Neurobiol Aging 2014;35:1334-1344.
21.
De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, et al: Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci 2014;17:1156-1163.
22.
Chen C, Zhang C, Cheng L, Reilly JL, Bishop JR, Sweeney JA, et al: Correlation between DNA methylation and gene expression in the brains of patients with bipolar disorder and schizophrenia. Bipolar Disord 2014;16:790-799.
23.
Dong E, Ruzicka WB, Grayson DR, Guidotti A: DNA-methyltransferase1 (DNMT1) binding to CpG rich GABAergic and BDNF promoters is increased in the brain of schizophrenia and bipolar disorder patients. Schizophr Res 2014;167:35-41.
24.
Pidsley R, Viana J, Hannon E, Spiers H, Troakes C, Al-Saraj S, et al: Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia. Genome Biol 2014;15:483.
25.
Grillo MA, Colombatto S: S-adenosylmethionine and its products. Amino Acids 2008;34:187-193.
26.
Williams RJ, Berry LJ, Beerstecher E: Individual metabolic patterns, alcoholism, genetotrophic diseases. Proc Natl Acad Sci U S A 1949;35:265-271.
27.
Rush EC, Katre P, Yajnik CS: Vitamin B12: one carbon metabolism, fetal growth and programming for chronic disease. Eur J Clin Nutr 2014;68:2-7.
28.
Blasco C, Caballería J, Deulofeu R, Lligoña A, Parés A, Lluis JM, Gual A, Rodés J: Prevalence and mechanisms of hyperhomocysteinemia in chronic alcoholics. Alcohol Clin Exp Res 2005;29:1044-1048.
29.
Chen CH, Pan CH, Chen CC, Huang MC: Increased oxidative DNA damage in patients with alcohol dependence and its correlation with alcohol withdrawal severity. Alcohol Clin Exp Res 2011;35:338-344.
30.
Pogribny IP, Rusyn I: Role of epigenetic aberrations in the development and progression of human hepatocellular carcinoma. Cancer Lett 2014;342:223-230.
31.
Foroud T, Wetherill LF, Liang T, Dick DM, Hesselbrock V, Kramer J, et al: Association of alcohol craving with alpha-synuclein (SNCA). Alcohol Clin Exp Res 2007;31:537-545.
32.
Jiang W, Li J, Zhang Z, Wang H, Wang Z: Epigenetic upregulation of alpha-synuclein in the rats exposed to methamphetamine. Eur J Pharmacol 2014;745:243-248.
33.
Taqi MM, Bazov I, Watanabe H, Sheedy D, Harper C, Alkass K, et al: Prodynorphin CpG-SNPs associated with alcohol dependence: elevated methylation in the brain of human alcoholics. Addict Biol 2011;16:499-509.
34.
Barker JM, Zhang Y, Wang F, Taylor JR, Zhang H: Ethanol-induced Htr3a promoter methylation changes in mouse blood and brain. Alcohol Clin Exp Res 2013;37(suppl 1):E101-E107.
35.
Zhang H, Herman AI, Kranzler HR, Anton RF, Zhao H, Zheng W, Gelernter J: Array-based profiling of DNA methylation changes associated with alcohol dependence. Alcohol Clin Exp Res 2013;37(suppl 1):E108-E115.
36.
Weng JT, Wu LS, Lee CS, Hsu PW, Cheng AT: Integrative epigenetic profiling analysis Identifies DNA methylation changes associated with chronic alcohol consumption. Comput Biol Med 2015;64:299-306.
37.
Zhang R, Miao Q, Wang C, Zhao R, Li W, Haile CN: Genome-wide DNA methylation analysis in alcohol dependence. Addict Biol 2013;18:392-403.
38.
Maier SE, Cramer JA, West JR, Sohrabji F: Alcohol exposure during the first two trimesters equivalent alters granule cell number and neurotrophin expression in the developing rat olfactory bulb. J Neurobiol 1999;41:414-423.
39.
Vallés S, Pitarch J, Renau-Piqueras J, Guerri C: Ethanol exposure affects glial fibrillary acidic protein gene expression and transcription during rat brain development. J Neurochem 1997;69:2484-2493.
40.
Hicks SD, Middleton FA, Miller MW: Ethanol-induced methylation of cell cycle genes in neural stem cells. J Neurochem 2010;114:1767-1780.
41.
Biermann T, Reulbach U, Lenz B, Frieling H, Muschler M, Hillemacher T, et al: N-methyl-D-aspartate 2b receptor subtype (NR2B) promoter methylation in patients during alcohol withdrawal. J Neural Transm (Vienna) 2009;116:615-622.
42.
Qiang M, Denny A, Chen J, Ticku MK, Yan B, Henderson G: The site specific demethylation in the 5ʼ-regulatory area of NMDA receptor 2B subunit gene associated with CIE-induced up-regulation of transcription. PLoS One 2010;5:e8798.
43.
Bernstein BE, Meissner A, Lander ES: The mammalian epigenome. Cell 2007;128:669-681.
44.
Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ: Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 1997;389:251-260.
45.
Pattaroni C, Jacob C: Histone methylation in the nervous system: functions and dysfunctions. Mol Neurobiol 2013;47:740-756.
46.
Balemans MC, Huibers MM, Eikelenboom NW, Kuipers AJ, van Summeren RC, Pijpers MM, Tachibana M, Shinkai Y, van Bokhoven H, Van der Zee CE: Reduced exploration, increased anxiety, and altered social behavior: autistic-like features of euchromatin histone methyltransferase 1 heterozygous knockout mice. Behav Brain Res 2010;208:47-55.
47.
Huang HS, Matevossian A, Whittle C, Kim SY, Schumacher A, Baker SP, et al: Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters. J Neurosci 2007;27:11254-11262.
48.
Gupta S, Kim SY, Artis S, Molfese DL, Schumacher A, Sweatt JD, et al: Histone methylation regulates memory formation. J Neurosci 2010;30:3589-3599.
49.
Stadler F, Kolb G, Rubusch L, Baker SP, Jones EG, Akbarian S: Histone methylation at gene promoters is associated with developmental regulation and region-specific expression of ionotropic and metabotropic glutamate receptors in human brain. J Neurochem 2005;94:324-336.
50.
Subbanna S, Basavarajappa BS: Pre-administration of G9a/GLP inhibitor during synaptogenesis prevents postnatal ethanol-induced LTP deficits and neurobehavioral abnormalities in adult mice. Exp Neurol 2014;261:34-43.
51.
Zhou Z, Yuan Q, Mash DC, Goldman D: Substance-specific and shared transcription and epigenetic changes in the human hippocampus chronically exposed to cocaine and alcohol. Proc Natl Acad Sci U S A 2011;108:6626-6631.
52.
Subbanna S, Shivakumar M, Umapathy NS, Saito M, Mohan PS, Kumar A, et al: G9a-mediated histone methylation regulates ethanol-induced neurodegeneration in the neonatal mouse brain. Neurobiol Dis 2013;54:475-485.
53.
Subbanna S, Nagre NN, Shivakumar M, Umapathy NS, Psychoyos D, Basavarajappa BS: Ethanol induced acetylation of histone at G9a exon1 and G9a-mediated histone H3 dimethylation leads to neurodegeneration in neonatal mice. Neuroscience 2014;258:422-432.
54.
Pascual M, Do Couto BR, Alfonso-Loeches S, Aguilar MA, Rodriguez-Arias M, Guerri C: Changes in histone acetylation in the prefrontal cortex of ethanol-exposed adolescent rats are associated with ethanol-induced place conditioning. Neuropharmacology 2012;62:2309-2319.
55.
Kumar A, Choi KH, Renthal W, Tsankova NM, Theobald DE, Truong HT, et al: Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 2005;48:303-314.
56.
Mashayekhi FJ, Rasti M, Rahvar M, Mokarram P, Namavar MR, Owji AA: Expression levels of the BDNF gene and histone modifications around its promoters in the ventral tegmental area and locus ceruleus of rats during forced abstinence from morphine. Neurochem Res 2012;37:1517-1523.
57.
Robison AJ, Nestler EJ: Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci 2011;12:623-637.
58.
Hebbes TR, Thorne AW, Crane-Robinson C: A direct link between core histone acetylation and transcriptionally active chromatin. EMBO J 1988;7:1395-1402.
59.
Ivanov M, Barragan I, Ingelman-Sundberg M: Epigenetic mechanisms of importance for drug treatment. Trends Pharmacol Sci 2014;35:384-396.
60.
Abel T, Zukin RS: Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders. Curr Opin Pharmacol 2008;8:57-64.
61.
Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, et al: HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 2009;459:55-60.
62.
Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC, Cota P, et al: Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 2010;328:753-756.
63.
Hsieh J, Gage FH: Chromatin remodeling in neural development and plasticity. Curr Opin Cell Biol 2005;17:664-671.
64.
Maurice T, Duclot F, Meunier J, Naert G, Givalois L, Meffre J, et al: Altered memory capacities and response to stress in p300/CBP-associated factor (PCAF) histone acetylase knockout mice. Neuropsychopharmacology 2008;33:1584-1602.
65.
Chen G, Zou X, Watanabe H, van Deursen JM, Shen J: CREB binding protein is required for both short-term and long-term memory formation. J Neurosci 2010;30:13066-13077.
66.
Caccamo A, Maldonado MA, Bokov AF, Majumder S, Oddo S: CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 2010;107:22687-22692.
67.
Narayan PJ, Lill C, Faull R, Curtis MA, Dragunow M: Increased acetyl and total histone levels in post-mortem Alzheimer's disease brain. Neurobiol Dis 2015;74:281-294.
68.
Pandey SC, Ugale R, Zhang H, Tang L, Prakash A: Brain chromatin remodeling: a novel mechanism of alcoholism. J Neurosci 2008;28:3729-3737.
69.
Sakharkar AJ, Zhang H, Tang L, Shi G, Pandey SC: Histone deacetylases (HDAC)-induced histone modifications in the amygdala: a role in rapid tolerance to the anxiolytic effects of ethanol. Alcohol Clin Exp Res 2012;36:61-71.
70.
Pascual M, Boix J, Felipo V, Guerri C: Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat. J Neurochem 2009;108:920-931.
71.
Guo W, Crossey EL, Zhang L, Zucca S, George OL, Valenzuela CF, et al: Alcohol exposure decreases CREB binding protein expression and histone acetylation in the developing cerebellum. PLoS One 2011;6:e19351.
72.
Shibasaki M, Mizuno K, Kurokawa K, Ohkuma S: Enhancement of histone acetylation in midbrain of mice with ethanol physical dependence and its withdrawal. Synapse 2011;65:1244-1250.
73.
Renthal W, Nestler EJ: Histone acetylation in drug addiction. Semin Cell Dev Biol 2009;20:387-394.
74.
Liokatis S, Stützer A, Elsässer SJ, Theillet FX, Klingberg R, van Rossum B, et al: Phosphorylation of histone H3 Ser10 establishes a hierarchy for subsequent intramolecular modification events. Nat Struct Mol Biol 2012;19:819-823.
75.
Mori T, Wakabayashi T, Ogawa H, Hirahara Y, Koike T, Yamada H: Increased histone H3 phosphorylation in neurons in specific brain structures after induction of status epilepticus in mice. PLoS One 2013;8:e77710.
76.
Pavlova MB, Dyuzhikova NA, Shiryaeva NV, Savenko YN, Vaido AI: Effect of long-term stress on H3Ser10 histone phosphorylation in neuronal nuclei of the sensorimotor cortex and midbrain reticular formation in rats with different nervous system excitability. Bull Exp Biol Med 2013;155:373-375.
77.
Aroor AR, Restrepo RJ, Kharbanda KK, Shukla SD: Epigenetic histone modifications in a clinically relevant rat model of chronic ethanol-binge-mediated liver injury. Hepatol Int 2014;8(suppl 2):421-430.
78.
Pickart CM: Mechanisms underlying ubiquitination. Annu Rev Biochem 2001;70:503-533.
79.
Hammond-Martel I, Yu H, Affar El B: Roles of ubiquitin signaling in transcription regulation. Cell Signal 2012;24:410-421.
80.
Goldknopf IL, Taylor CW, Baum RM, Yeoman LC, Olson MO, Prestayko AW, Busch H: Isolation and characterization of protein A24, a ‘histone-like' non-histone chromosomal protein. J Biol Chem 1975;250:7182-7187.
81.
Jones JM, Bhattacharyya A, Simkus C, Vallieres B, Veenstra TD, Zhou M: The RAG1 V(D)J recombinase/ubiquitin ligase promotes ubiquitylation of acetylated, phosphorylated histone 3.3. Immunol Lett 2011;136:156-162.
82.
Wang H, Zhai L, Xu J, Joo HY, Jackson S, Erdjument-Bromage H, et al: Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage. Mol Cell 2006;22:383-394.
83.
Chandrasekharan MB, Huang F, Sun ZW: Ubiquitination of histone H2B regulates chromatin dynamics by enhancing nucleosome stability. Proc Natl Acad Sci U S A 2009;106:16686-16691.
84.
Ishino Y, Hayashi Y, Naruse M, Tomita K, Sanbo M, Fuchigami T, et al: Bre1a, a Histone H2B ubiquitin ligase, regulates the cell cycle and differentiation of neural precursor cells. J Neurosci 2014;34:3067-3078.
85.
Rubio MD, Wood K, Haroutunian V, Meador-Woodruff JH: Dysfunction of the ubiquitin proteasome and ubiquitin-like systems in schizophrenia. Neuropsychopharmacology 2013;38:1910-1920.
86.
Krumova P, Weishaupt JH: Sumoylation in neurodegenerative diseases. Cell Mol Life Sci 2013;70:2123-2138.
87.
Nisticò R, Ferraina C, Marconi V, Blandini F, Negri L, Egebjerg J, et al: Age-related changes of protein SUMOylation balance in the AβPP Tg2576 mouse model of Alzheimer's disease. Front Pharmacol 2014;5:63.
88.
Hu M, Wang F, Li X, Rogers CQ, Liang X, Finck BN, et al: Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice. Hepatology 2012;55:437-446.
89.
El Fatimy R, Miozzo F, Le Mouël A, Abane R, Schwendimann L, Sabéran-Djoneidi D, et al: Heat shock factor 2 is a stress-responsive mediator of neuronal migration defects in models of fetal alcohol syndrome. EMBO Mol Med 2014;6:1043-1061.
90.
Rinn JL, Chang HY: Genome regulation by long noncoding RNAs. Annu Rev Biochem 2012;81:145-166.
91.
Pietrzykowski AZ, Friesen RM, Martin GE, Puig SI, Nowak CL, Wynne PM, Siegelmann HT, Treistman SN: Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol. Neuron 2008;59:274-287.
92.
Qi Y, Zhang M, Li H, Frank JA, Dai L, Liu H, Chen G: MicroRNA-29b regulates ethanol-induced neuronal apoptosis in the developing cerebellum through SP1/RAX/PKR cascade. J Biol Chem 2014;289:10201-10210.
93.
Nunez YO, Truitt JM, Gorini G, Ponomareva ON, Blednov YA, Harris RA, et al: Positively correlated miRNA-mRNA regulatory networks in mouse frontal cortex during early stages of alcohol dependence. BMC Genomics 2013;14:725.
94.
Darcq E, Warnault V, Phamluong K, Besserer GM, Liu F, Ron D: MicroRNA-30a-5p in the prefrontal cortex controls the transition from moderate to excessive alcohol consumption. Mol Psychiatry 2015;20:1219-1231.
95.
Melka MG, Laufer BI, McDonald P, Castellani CA, Rajakumar N, O'Reilly R, et al: The effects of olanzapine on genome-wide DNA methylation in the hippocampus and cerebellum. Clin Epigenetics 2014;6:1.
96.
Medical University of Vienna: Effects of Creatine Supplementation in Rett Syndrome: A Randomized, Placebo-controlled Trial, 2009. https://clinicaltrials.gov/ct2/show/record/NCT01147575?term=NCT01147575&rank=1>.
97.
Warnault V, Darcq E, Levine A, Barak S, Ron D: Chromatin remodeling - a novel strategy to control excessive alcohol drinking. Transl Psychiatry 2013;3:e231.
98.
University Hospital, Bordeaux: Rubinstein-Taybi Syndrome: Functional Imaging and Therapeutic, 2014. https://clinicaltrials.gov/ct2/show/NCT01619644?term=NCT01619644&rank=1.
99.
Al Ameri M, Al Mansouri S, Al Maamari A, Bahi A: The histone deacetylase (HDAC) inhibitor valproic acid reduces ethanol consumption and ethanol-conditioned place preference in rats. Brain Res 2014;1583:122-131.
100.
Peter CJ, Akbarian S: Balancing histone methylation activities in psychiatric disorders. Trends Mol Med 2011;17:372-379.
101.
Walker DM, Cates HM, Heller EA, Nestler EJ: Regulation of chromatin states by drugs of abuse. Curr Opin Neurobiol 2015;30:112-121.
102.
Kubicek S, O'Sullivan RJ, August EM, Hickey ER, Zhang Q, Teodoro ML, et al: Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell 2007;25:473-481.
103.
Maze I, Covington HE 3rd, Dietz DM, LaPlant Q, Renthal W, Russo SJ, et al: Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science 2010;327:213-216.
104.
Arora DS, Nimitvilai S, Teppen TL, McElvain MA, Sakharkar AJ, You C, Pandey SC, Brodie MS: Hyposensitivity to gamma-aminobutyric acid in the ventral tegmental area during alcohol withdrawal: reversal by histone deacetylase inhibitors. Neuropsychopharmacology 2013;38:1674-1684.
105.
D'Addario C, Caputi FF, Ekström TJ, Di Benedetto M, Maccarrone M, Romualdi P, Candeletti S: Ethanol induces epigenetic modulation of prodynorphin and pronociceptin gene expression in the rat amygdala complex. J Mol Neurosci 2013;49:312-319.
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