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Epigenetic Mechanisms Underlying Pathobiology of Alcohol Use Disorder

  • The Pathobiology of Alcohol Consumption (P Molina and M Ronis, Section Editors)
  • Published:
Current Pathobiology Reports

Abstract

Purpose of Review

Chronic alcohol use is a worldwide problem with multifaceted consequences including multiplying medical costs and sequelae, societal effects like drunk driving and assault, and lost economic productivity. These large-scale outcomes are driven by the consumption of ethanol, a small permeable molecule that has myriad effects in the human body, particularly in the liver and brain. In this review, we have summarized the effects of acute and chronic alcohol consumption on epigenetic mechanisms that may drive pathobiology of alcohol use disorder (AUD) while identifying areas of need for future research.

Recent Findings

Epigenetics has emerged as an interesting field of biology at the intersection of genetics and the environment, and ethanol, in particular, has been identified as a potent modulator of the epigenome with various effects on DNA methylation, histone modifications, and non-coding RNAs. These changes alter chromatin dynamics and regulate gene expression that contribute to behavioral and physiological changes leading to the development of AUD psychopathology and cancer pathology.

Summary

Evidence and discussion presented here from preclinical results and available translational studies have increased our knowledge of the epigenetic effects of alcohol consumption. These studies have identified targets that can be used to develop better therapies to reduce chronic alcohol abuse and mitigate its societal burden and pathophysiology.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. McGovern PE, Zhang J, Tang J, Zhang Z, Hall GR, Moreau RA, et al. Fermented beverages of pre- and proto-historic China. Proc Natl Acad Sci. 2004;101(51):17593–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Griswold MG, Fullman N, Hawley C, Arian N, Zimsen SRM, Tymeson HD, et al. Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2018;392(10152):1015–35.

  3. Rehm J, Gmel G, Sempos CT, Trevisan M. Alcohol-related morbidity and mortality. Alcohol Res Health. 2003;27(1):39–51.

    PubMed  PubMed Central  Google Scholar 

  4. Harris RA, Trudell JR, Mihic SJ. Ethanol’s molecular targets. Sci Signal. 2008;1(28):re7.

    PubMed  PubMed Central  Google Scholar 

  5. Geil CR, Hayes DM, McClain JA, Liput DJ, Marshall SA, Chen KY, et al. Alcohol and adult hippocampal neurogenesis: promiscuous drug, wanton effects. Prog Neuro-Psychopharmacol Biol Psychiatry. 2014;54:103–13.

    CAS  Google Scholar 

  6. • Pandey SC, Kyzar EJ, Zhang H. Epigenetic basis of the dark side of alcohol addiction. Neuropharmacology. 2017;122:74–84 This review article integrates the concept of allostasis of epigenetic changes in the amygdala, a framework to understand negative affective state of alcohol use disorder by targeting windows of plasticity. These ideas help to better understand why epigenetic effects of acute and chronic ethanol are crucial for discovering better treatments for alcohol use disorder and related sequelae.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Yoshimura M, Pearson S, Kadota Y, Gonzalez CE. Identification of ethanol responsive domains of adenylyl cyclase. Alcohol Clin Exp Res. 2006;30(11):1824–32.

    CAS  PubMed  Google Scholar 

  8. Das R, Esposito V, Abu-Abed M, Anand GS, Taylor SS, Melacini G. cAMP activation of PKA defines an ancient signaling mechanism. Proc Natl Acad Sci U S A. 2007;104(1):93–8.

    CAS  PubMed  Google Scholar 

  9. Pandey SC. Neuronal signaling systems and ethanol dependence. Mol Neurobiol. 1998;17(1):1–15.

    CAS  PubMed  Google Scholar 

  10. Misra K, Pandey SC. The decreased cyclic-AMP dependent-protein kinase A function in the nucleus accumbens: a role in alcohol drinking but not in anxiety-like behaviors in rats. Neuropsychopharmacology. 2006;31(7):1406–19.

    CAS  PubMed  Google Scholar 

  11. Pandey SC, Roy A, Zhang H. The decreased phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein in the central amygdala acts as a molecular substrate for anxiety related to ethanol withdrawal in rats. Alcohol Clin Exp Res. 2003;27(3):396–409.

    CAS  PubMed  Google Scholar 

  12. Pandey SC, Zhang H, Roy A, Xu T. Deficits in amygdaloid cAMP-responsive element–binding protein signaling play a role in genetic predisposition to anxiety and alcoholism. J Clin Invest. 2005;115(10):2762–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kumar S, Porcu P, Werner DF, Matthews DB, Diaz-Granados JL, Helfand RS, et al. The role of GABA(A) receptors in the acute and chronic effects of ethanol: a decade of progress. Psychopharmacology. 2009;205(4):529–64.

  14. Lovinger DM, White G, Weight FF. Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science. 1989;243(4899):1721–4.

    CAS  PubMed  Google Scholar 

  15. Ron D, Messing RO. Signaling pathways mediating alcohol effects. Curr Top Behav Neurosci. 2013;13:87–126.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci. 2007;8(5):355–67.

    CAS  PubMed  Google Scholar 

  17. Shukla SD, Lim RW. Epigenetic effects of ethanol on the liver and gastrointestinal system. Alcohol Res Curr Rev. 2013;35(1):47–55.

    Google Scholar 

  18. Waddington CH. The strategy of the genes: a discussion of some aspects of theoretical biology. Allen & Unwin; 1957. 280 p.

  19. McEwen BS. Allostasis and the epigenetics of brain and body health over the life course: the brain on stress. JAMA Psychiatry. 2017;74(6):551–2.

    PubMed  Google Scholar 

  20. Szutorisz H, Hurd YL. Epigenetic effects of cannabis exposure. Biol Psychiatry. 2016;79(7):586–94.

    CAS  PubMed  Google Scholar 

  21. Krishnan HR, Sakharkar AJ, Teppen TL, Berkel TDM, Pandey SC. The epigenetic landscape of alcoholism. Int Rev Neurobiol. 2014;115:75–116.

    PubMed  PubMed Central  Google Scholar 

  22. Ponomarev I. Epigenetic control of gene expression in the alcoholic brain. Alcohol Res Curr Rev. 2013;35(1):69–76.

    Google Scholar 

  23. Hsu F-M, Gohain M, Chang P, Lu J-H, Chen P-Y. Chapter 4 - bioinformatics of epigenomic data generated from next-generation sequencing. In: Epigenetics in Human Disease. 2nd ed: Academic Press; 2018. p. 65–106. (Translational Epigenetics; vol. 6).

  24. Hamamoto R, Komatsu M, Takasawa K, Asada K, Kaneko S. Epigenetics analysis and integrated analysis of multiomics data, including epigenetic data, using artificial intelligence in the era of precision medicine. Biomolecules. 2019;10(1):Pii: E62.

    Google Scholar 

  25. Bagot RC, Labonté B, Peña CJ, Nestler EJ. Epigenetic signaling in psychiatric disorders: stress and depression. Dialogues Clin Neurosci. 2014;16(3):281–95.

    PubMed  PubMed Central  Google Scholar 

  26. Feng J, Nestler EJ. Epigenetic mechanisms of drug addiction. Curr Opin Neurobiol. 2013;23(4):521–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358(11):1148–59.

    CAS  PubMed  Google Scholar 

  28. French SW. Epigenetic events in liver cancer resulting from alcoholic liver disease. Alcohol Res Curr Rev. 2013;35(1):57–67.

    Google Scholar 

  29. Mahnke AH, Miranda RC, Homanics GE. Epigenetic mediators and consequences of excessive alcohol consumption. Alcohol. 2017;60:1–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Toh TB, Lim JJ, Chow EK-H. Epigenetics of hepatocellular carcinoma. Clin Transl Med. 2019;6:8.

    Google Scholar 

  31. Uysal F, Ozturk S, Akkoyunlu G. DNMT1, DNMT3A and DNMT3B proteins are differently expressed in mouse oocytes and early embryos. J Mol Histol. 2017;48(5–6):417–26.

    CAS  PubMed  Google Scholar 

  32. Mahmoud AM, Ali MM. Methyl donor micronutrients that modify DNA methylation and cancer outcome. Nutrients. 2019;13:11(3).

    Google Scholar 

  33. Li E, Zhang Y. DNA methylation in mammals. Cold Spring Harb Perspect Biol. 2014 May;6(5).

  34. Boyes J, Bird A. DNA methylation inhibits transcription indirectly via a methyl-CpG binding protein. Cell. 1991;64(6):1123–34.

    CAS  PubMed  Google Scholar 

  35. Watt F, Molloy PL. Cytosine methylation prevents binding to DNA of a HeLa cell transcription factor required for optimal expression of the adenovirus major late promoter. Genes Dev. 1988;2(9):1136–43.

    CAS  PubMed  Google Scholar 

  36. Cedar H, Bergman Y. Programming of DNA methylation patterns. Annu Rev Biochem. 2012;81:97–117.

    CAS  PubMed  Google Scholar 

  37. Guo JU, Su Y, Zhong C, Ming G, Song H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011;145(3):423–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Bednar J, Horowitz RA, Grigoryev SA, Carruthers LM, Hansen JC, Koster AJ, et al. Nucleosomes, linker DNA, and linker histone form a unique structural motif that directs the higher-order folding and compaction of chromatin. Proc Natl Acad Sci. 1998;95(24):14173–8.

  39. Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature. 1997;389(6648):251–60.

    CAS  PubMed  Google Scholar 

  40. Hergeth SP, Schneider R. The H1 linker histones: multifunctional proteins beyond the nucleosomal core particle. EMBO Rep. 2015;16(11):1439–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Renthal W, Nestler EJ. Chromatin regulation in drug addiction and depression. Dialogues Clin Neurosci. 2009;11(3):257–68.

    PubMed  PubMed Central  Google Scholar 

  42. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21(3):381–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kouzarides T. Chromatin modifications and their function. Cell. 2007;128(4):693–705.

    CAS  PubMed  Google Scholar 

  44. Jakovcevski M, Akbarian S. Epigenetic mechanisms in neurological disease. Nat Med. 2012;18(8):1194–204.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M. Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov. 2012;11(5):384–400.

    CAS  PubMed  Google Scholar 

  46. Nightingale KP, O’Neill LP, Turner BM. Histone modifications: signalling receptors and potential elements of a heritable epigenetic code. Curr Opin Genet Dev. 2006;16(2):125–36.

    CAS  PubMed  Google Scholar 

  47. Costa FF. Non-coding RNAs, epigenetics and complexity. Gene. 2008;410(1):9–17.

    CAS  PubMed  Google Scholar 

  48. Kim T-K, Hemberg M, Gray JM, Costa AM, Bear DM, Wu J, et al. Widespread transcription at neuronal activity-regulated enhancers. Nature. 2010;465(7295):182–7.

  49. Kolovos P, Knoch TA, Grosveld FG, Cook PR, Papantonis A. Enhancers and silencers: an integrated and simple model for their function. Epigenetics Chromatin. 2012;5:1.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Robison AJ, Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci. 2011;12(11):623–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. . Bohnsack JP, Teppen T, Kyzar EJ, Dzitoyeva S, Pandey SC. The lncRNA BDNF-AS is an epigenetic regulator in the human amygdala in early onset alcohol use disorders. Transl Psychiatry. 2019;6:9 This translational study outlines an epigenetic mechanism in the human post-mortem amygdala by which alcohol exposure in adolescence promotes persistent BDNF dysregulation and resultant behavioral dysfunction by a naturally occurring lncRNA and its associated epigenetic regulatory mechanisms.

    Google Scholar 

  52. Jiang M-C, Ni J-J, Cui W-Y, Wang B-Y, Zhuo W. Emerging roles of lncRNA in cancer and therapeutic opportunities. Am J Cancer Res. 2019;9(7):1354–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Guttman M, Rinn JL. Modular regulatory principles of large non–coding RNAs. Nature. 2012;482(7385):339–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature. 2009;458(7235):223–7.

  55. Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A. 2009;106(28):11667–72.

  56. Mayfield RD. Emerging roles for ncRNAs in alcohol use disorders. Alcohol. 2017;60:31–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Li X, Egervari G, Wang Y, Berger SL, Lu Z. Regulation of chromatin and gene expression by metabolic enzymes and metabolites. Nat Rev Mol Cell Biol. 2018;19(9):563–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Lee KK, Workman JL. Histone acetyltransferase complexes: one size doesn’t fit all. Nat Rev Mol Cell Biol. 2007;8(4):284–95.

    CAS  PubMed  Google Scholar 

  59. Kim J-S, Shukla SD. Acute in vivo effect of ethanol (binge drinking) on histone H3 modifications in rat tissues. Alcohol Alcohol. 2006;41(2):126–32.

    CAS  PubMed  Google Scholar 

  60. •• Mews P, Egervari G, Nativio R, Sidoli S, Donahue G, Lombroso SI, et al. Alcohol metabolism contributes to brain histone acetylation. Nature. 2019;574(7780):717–21 This groundbreaking study uses in vivo stable isotope labeling to demonstrate acetyl groups derived from ethanol consumption contribute to rapid acetylation of histones in the brain. Furthermore, chromatin-bound acetyl-CoA synthase in the hippocampus is demonstrated to be necessary for alcohol-associated learning, directly linking an ethanol-induced epigenetic mechanism to transcriptomic and behavioral impairment.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kriss CL, Gregory-Lott E, Storey AJ, Tackett AJ, Wahls WP, Stevens SM. In vivo metabolic tracing demonstrates the site-specific contribution of hepatic ethanol metabolism to histone acetylation. Alcohol Clin Exp Res. 2018;42(10):1909–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Zakhari S. Alcohol metabolism and epigenetics changes. Alcohol Res Curr Rev. 2013;35(1):6–16.

    Google Scholar 

  63. Pandey SC, Bohnsack JP. Alcohol makes its epigenetic marks. Cell Metab. 2020;31(2):213–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Berkel TDM, Pandey SC. Emerging role of epigenetic mechanisms in alcohol addiction. Alcohol Clin Exp Res. 2017;41(4):666–80.

    PubMed  PubMed Central  Google Scholar 

  65. D’Addario C, Caputi FF, Ekström TJ, Di Benedetto M, Maccarrone M, Romualdi P, et al. Ethanol induces epigenetic modulation of prodynorphin and pronociceptin gene expression in the rat amygdala complex. J Mol Neurosci MN. 2013;49(2):312–9.

    PubMed  Google Scholar 

  66. Pandey SC, Zhang H, Ugale R, Prakash A, Xu T, Misra K. Effector immediate-early gene arc in the amygdala plays a critical role in alcoholism. J Neurosci. 2008;28(10):2589–600.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Pandey SC, Ugale R, Zhang H, Tang L, Prakash A. Brain chromatin remodeling: a novel mechanism of alcoholism. J Neurosci. 2008;28(14):3729–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 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(1):61–71.

    CAS  PubMed  Google Scholar 

  69. Sakharkar AJ, Zhang H, Tang L, Baxstrom K, Shi G, Moonat S, et al. Effects of histone deacetylase inhibitors on amygdaloid histone acetylation and neuropeptide Y expression: a role in anxiety-like and alcohol-drinking behaviors. Int J Neuropsychopharmacol. 2014;17(8):1207–20.

  70. Berkel TDM, Zhang H, Teppen T, Sakharkar AJ, Pandey SC. Essential role of histone methyltransferase G9a in rapid tolerance to the anxiolytic effects of ethanol. Int J Neuropsychopharmacol. 2019;22(4):292–302.

    CAS  PubMed  Google Scholar 

  71. Finegersh A, Homanics GE. Acute ethanol alters multiple histone modifications at model gene promoters in the cerebral cortex. Alcohol Clin Exp Res. 2014;38(7):1865–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Wolstenholme JT, Warner JA, Capparuccini MI, Archer KJ, Shelton KL, Miles MF. Genomic analysis of individual differences in ethanol drinking: evidence for non-genetic factors in C57BL/6 mice. PLoS One. 2011;16:6(6).

    Google Scholar 

  73. Dulman RS, Auta J, Teppen T, Pandey SC. Acute ethanol produces ataxia and induces Fmr1 expression via histone modifications in the rat cerebellum. Alcohol Clin Exp Res. 2019;43(6):1191–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Teppen TL, Krishnan HR, Zhang H, Sakharkar AJ, Pandey SC. The potential role of amygdaloid microRNA-494 in alcohol-induced anxiolysis. Biol Psychiatry. 2016;80(9):711–9.

    CAS  PubMed  Google Scholar 

  75. Clark SL, Costin BN, Chan RF, Johnson AW, Xie L, Jurmain JL, et al. A whole methylome study of ethanol exposure in brain and blood: an exploration of the utility of peripheral blood as proxy tissue for brain in alcohol methylation studies. Alcohol Clin Exp Res. 2018;42(12):2360–8.

  76. Irwin C, Mienie LJ, Wevers RA, Mason S, Westerhuis JA, van Reenen M, et al. GC–MS-based urinary organic acid profiling reveals multiple dysregulated metabolic pathways following experimental acute alcohol consumption. Sci Rep. 2018;10:8.

    Google Scholar 

  77. Teschke R. Alcoholic liver disease: alcohol metabolism, cascade of molecular mechanisms, cellular targets, and clinical aspects. Biomedicines. 2018;12:6(4).

    Google Scholar 

  78. Kriss CL, Gregory-Lott E, Storey AJ, Tackett AJ, Wahls WP, Stevens SM. In vivo metabolic tracing demonstrates the site-specific contribution of hepatic ethanol metabolism to histone acetylation. Alcohol Clin Exp Res. 2018;42(10):1909–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Shukla SD, Restrepo R, Fish P, Lim RW, Ibdah JA. Different mechanisms for histone acetylation by ethanol and its metabolite acetate in rat primary hepatocytes. J Pharmacol Exp Ther. 2015;354(1):18–23.

    CAS  PubMed  Google Scholar 

  80. Choudhury M, Park P-H, Jackson D, Shukla SD. Evidence for the role of oxidative stress in the acetylation of histone H3 by ethanol in rat hepatocytes. Alcohol. 2010;44(6):531–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Restrepo RJ, Lim RW, Korthuis RJ, Shukla SD. Binge alcohol alters PNPLA3 levels in liver through epigenetic mechanism involving histone H3 acetylation. Alcohol. 2017;60:77–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Kirpich I, Ghare S, Zhang J, Gobejishvili L, Kharebava G, Barve SJ, et al. Binge alcohol-induced microvesicular liver steatosis and injury are associated with down-regulation of hepatic Hdac 1, 7, 9, 10, 11 and up-regulation of Hdac 3. Alcohol Clin Exp Res. 2012;36(9):1578–86.

  83. Kirpich I, Zhang J, Gobejishvili L, Kharebava G, Barker D, Ghare S, et al. Binge ethanol-induced HDAC3 down-regulates Cpt1α expression leading to hepatic steatosis and injury. Alcohol Clin Exp Res. 2013;37(11):1920–9.

  84. Niculescu MD, Zeisel SH. Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr. 2002;132(8):2333S–5S.

    CAS  PubMed  Google Scholar 

  85. Blasco C, Caballería J, Deulofeu R, Lligoña A, Parés A, Lluis JM, et al. Prevalence and mechanisms of hyperhomocysteinemia in chronic alcoholics. Alcohol Clin Exp Res. 2005;29(6):1044–8.

    CAS  PubMed  Google Scholar 

  86. Lu SC, Huang ZZ, Yang H, Mato JM, Avila MA, Tsukamoto H. Changes in methionine adenosyltransferase and S-adenosylmethionine homeostasis in alcoholic rat liver. Am J Physiol Gastrointest Liver Physiol. 2000;279(1):G178–85.

    CAS  PubMed  Google Scholar 

  87. Auta J, Zhang H, Pandey SC, Guidotti A. Chronic alcohol exposure differentially alters one-carbon metabolism in rat liver and brain. Alcohol Clin Exp Res. 2017 ;41(6):1105–11.

  88. Lu SC, Mato JM. S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev. 2012;92(4):1515–42.

    CAS  PubMed  Google Scholar 

  89. Chen C-H, Pan C-H, Chen C-C, Huang M-C. Increased oxidative DNA damage in patients with alcohol dependence and its correlation with alcohol withdrawal severity. Alcohol Clin Exp Res. 2011;35(2):338–44.

    CAS  PubMed  Google Scholar 

  90. Choi SW, Stickel F, Baik HW, Kim YI, Seitz HK, Mason JB. Chronic alcohol consumption induces genomic but not p53-specific DNA hypomethylation in rat colon. J Nutr. 1999;129(11):1945–50.

    CAS  PubMed  Google Scholar 

  91. Hamid A, Wani NA, Kaur J. New perspectives on folate transport in relation to alcoholism-induced folate malabsorption--association with epigenome stability and cancer development. FEBS J. 2009;276(8):2175–91.

    CAS  PubMed  Google Scholar 

  92. Kendler KS, Prescott CA, Myers J, Neale MC. The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Arch Gen Psychiatry. 2003;60(9):929–37.

    PubMed  Google Scholar 

  93. Gavin DP, Hashimoto JG, Lazar NH, Carbone L, Crabbe JC, Guizzetti M. Stable histone methylation changes at proteoglycan network genes following ethanol exposure. Front Genet. 2018;9.

  94. Stragier E, Massart R, Salery M, Hamon M, Geny D, Martin V, et al. Ethanol-induced epigenetic regulations at the Bdnf gene in C57BL/6J mice. Mol Psychiatry. 2015;20(3):405–12.

  95. Zeng K, Xie A, Zhang X, Zhong B, Liu X, Hao W. Chronic alcohol treatment-induced GABA-Aα5 histone H3K4 trimethylation upregulation leads to increased GABA-Aα5 expression and susceptibility to alcohol addiction in the offspring of Wistar rats. Front Psychiatry. 2018;9.

  96. Finegersh A, Homanics GE. Paternal alcohol exposure reduces alcohol drinking and increases behavioral sensitivity to alcohol selectively in male offspring. PLoS One. 2014;4:9(6).

    Google Scholar 

  97. Verhulst B, Neale MC, Kendler KS. The heritability of alcohol use disorders: a meta-analysis of twin and adoption studies. Psychol Med. 2015;45(5):1061–72.

    CAS  PubMed  Google Scholar 

  98. Finegersh A, Rompala GR, Martin DIK, Homanics GE. Drinking beyond a lifetime: new and emerging insights into paternal alcohol exposure on subsequent generations. Alcohol Fayettev N. 2015;49(5):461–70.

    Google Scholar 

  99. Rompala GR, Homanics GE. Intergenerational effects of alcohol: a review of paternal preconception ethanol exposure studies and epigenetic mechanisms in the male germline. Alcohol Clin Exp Res. 2019;43(6):1032–45.

    PubMed  PubMed Central  Google Scholar 

  100. Qiang M, Denny A, Lieu M, Carreon S, Li J. Histone H3K9 modifications are a local chromatin event involved in ethanol-induced neuroadaptation of the NR2B gene. Epigenetics. 2011;6(9):1095–104.

    PubMed  PubMed Central  Google Scholar 

  101. Li D, Zhang Y, Zhang Y, Wang Q, Miao Q, Xu Y, et al. Correlation between the epigenetic modification of histone H3K9 acetylation of NR2B gene promoter in rat hippocampus and ethanol withdrawal syndrome. Mol Biol Rep. 2019;46(3):2867–75.

  102. Chen W-Y, Zhang H, Gatta E, Glover EJ, Pandey SC, Lasek AW. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) alleviates depression-like behavior and normalizes epigenetic changes in the hippocampus during ethanol withdrawal. Alcohol. 2019;78:79–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. You C, Vandegrift BJ, Zhang H, Lasek AW, Pandey SC, Brodie MS. Histone deacetylase inhibitor suberanilohydroxamic acid treatment reverses hyposensitivity to γ-aminobutyric acid in the ventral tegmental area during ethanol withdrawal. Alcohol Clin Exp Res. 2018;42(11):2160–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Moonat S, Sakharkar AJ, Zhang H, Tang L, Pandey SC. Aberrant HDAC2-mediated histone modifications and synaptic plasticity in the amygdala predisposes to anxiety and alcoholism. Biol Psychiatry. 2013;73(8):763–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Johnstone AL, Andrade NS, Barbier E, Khomtchouk BB, Rienas CA, Lowe K, et al. Dysregulation of the histone demethylase KDM6B in alcohol dependence is associated with epigenetic regulation of inflammatory signaling pathways. Addict Biol. 2019;1:e12816.

    Google Scholar 

  106. Barbier E, Johnstone AL, Khomtchouk BB, Tapocik JD, Pitcairn C, Rehman F, et al. Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2. Mol Psychiatry. 2017;22(12):1746–58.

  107. Barbier E, Tapocik JD, Juergens N, Pitcairn C, Borich A, Schank JR, et al. DNA methylation in the medial prefrontal cortex regulates alcohol-induced behavior and plasticity. J Neurosci. 2015;35(15):6153–64.

  108. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Sakharkar AJ, Kyzar EJ, Gavin DP, Zhang H, Chen Y, Krishnan HR, et al. Altered amygdala DNA methylation mechanisms after adolescent alcohol exposure contribute to adult anxiety and alcohol drinking. Neuropharmacology. 2019;157:107679.

  110. Morrison KE, Rodgers AB, Morgan CP, Bale TL. Epigenetic mechanisms in pubertal brain maturation. Neuroscience. 2014;264:17–24.

    CAS  PubMed  Google Scholar 

  111. DeWit DJ, Adlaf EM, Offord DR, Ogborne AC. Age at first alcohol use: a risk factor for the development of alcohol disorders. Am J Psychiatry. 2000;157(5):745–50.

    CAS  PubMed  Google Scholar 

  112. Kyzar EJ, Floreani C, Teppen TL, Pandey SC. Adolescent alcohol exposure: burden of epigenetic reprogramming, synaptic remodeling, and adult psychopathology. Front Neurosci. 2016;10.

  113. Pandey SC, Sakharkar AJ, Tang L, Zhang H. Potential role of adolescent alcohol exposure-induced amygdaloid histone modifications in anxiety and alcohol intake during adulthood. Neurobiol Dis. 2015;82:607–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Kyzar EJ, Zhang H, Sakharkar AJ, Pandey SC. Adolescent alcohol exposure alters lysine demethylase 1 (LSD1) expression and histone methylation in the amygdala during adulthood. Addict Biol. 2017;22(5):1191–204.

    CAS  PubMed  Google Scholar 

  115. Kyzar EJ, Zhang H, Pandey SC. Adolescent alcohol exposure epigenetically suppresses amygdala arc enhancer RNA expression to confer adult anxiety susceptibility. Biol Psychiatry. 2019;85(11):904–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Kyzar EJ, Bohnsack JP, Zhang H, Pandey SC. MicroRNA-137 drives epigenetic reprogramming in the adult amygdala and behavioral changes after adolescent alcohol exposure. eNeuro. 2019;1:6(6).

    Google Scholar 

  117. Sakharkar AJ, Vetreno RP, Zhang H, Kokare DM, Crews FT, Pandey SC. A role for histone acetylation mechanisms in adolescent alcohol exposure-induced deficits in hippocampal brain-derived neurotrophic factor expression and neurogenesis markers in adulthood. Brain Struct Funct. 2016;221(9):4691–703.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 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(7):2309–19.

    CAS  PubMed  Google Scholar 

  119. 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(5):1884–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Gatta E, Grayson DR, Auta J, Saudagar V, Dong E, Chen Y, et al. Genome-wide methylation in alcohol use disorder subjects: implications for an epigenetic regulation of the cortico-limbic glucocorticoid receptors (NR3C1). Mol Psychiatry. 2019;25:1–13.

    Google Scholar 

  121. Gatta E, Auta J, Gavin DP, Bhaumik DK, Grayson DR, Pandey SC, et al. Emerging role of one-carbon metabolism and DNA methylation enrichment on δ-containing GABAA receptor expression in the cerebellum of subjects with alcohol use disorders (AUD). Int J Neuropsychopharmacol. 2017 ;20(12):1013–2.

  122. Lohoff FW, Sorcher JL, Rosen AD, Mauro KL, Fanelli RR, Momenan R, et al. Methylomic profiling and replication implicates deregulation of PCSK9 in alcohol use disorder. Mol Psychiatry. 2018;23(9):1–11.

    Google Scholar 

  123. Witt SH, Frank J, Frischknecht U, Treutlein J, Streit F, Foo JC, et al. Acute alcohol withdrawal and recovery in men lead to profound changes in DNA methylation profiles: a longitudinal clinical study. Addiction. 2020;20:e15020.

    Google Scholar 

  124. Lin X-X, Lian G-H, Peng S-F, Zhao Q, Xu Y, Ou-Yang D-S, et al. Reversing epigenetic alterations caused by alcohol: a promising therapeutic direction for alcoholic liver disease. Alcohol Clin Exp Res. 2018;42(10):1863–73.

  125. Szabo G, Bala S. MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol. 2013;10(9):542–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. McDaniel K, Herrera L, Zhou T, Francis H, Han Y, Levine P, et al. The functional role of microRNAs in alcoholic liver injury. J Cell Mol Med. 2014;18(2):197–207.

  127. Li Y, Wang S, Ni H-M, Huang H, Ding W-X. Autophagy in alcohol-induced multiorgan injury: mechanisms and potential therapeutic targets. Biomed Res Int. 2014;2014:1–20.

    Google Scholar 

  128. Varela-Rey M, Woodhoo A, Martinez-Chantar M-L, Mato JM, Lu SC. Alcohol, DNA methylation, and cancer. Alcohol Res Curr Rev. 2013;35(1):25–35.

  129. Bala S, Csak T, Kodys K, Catalano D, Ambade A, Furi I, et al. Alcohol-induced miR-155 and HDAC11 inhibit negative regulators of the TLR4 pathway and lead to increased LPS responsiveness of Kupffer cells in alcoholic liver disease. J Leukoc Biol. 2017;102(2):487–98.

  130. Lee JS, Mukhopadhyay P, Matyas C, Trojnar E, Paloczi J, Yang YR, et al. PCSK9 inhibition as a novel therapeutic target for alcoholic liver disease. Sci Rep. 2019;9(1):1–16.

    Google Scholar 

  131. Nervi C, De Marinis E, Codacci-Pisanelli G. Epigenetic treatment of solid tumours: a review of clinical trials. Clin Epigenetics. 2015;7(1):127.

    PubMed  PubMed Central  Google Scholar 

  132. Bagnardi V, Rota M, Botteri E, Tramacere I, Islami F, Fedirko V, et al. Alcohol consumption and site-specific cancer risk: a comprehensive dose-response meta-analysis. Br J Cancer. 2015;112(3):580–93.

  133. Liu XS, Jaenisch R. Editing the epigenome to tackle brain disorders. Trends Neurosci. 2019;42(12):861–70.

    CAS  PubMed  Google Scholar 

  134. Joshi CR, Labhasetwar V, Ghorpade A. Destination brain: the past, present, and future of therapeutic gene delivery. J NeuroImmune Pharmacol. 2017;12(1):51–83.

    PubMed  PubMed Central  Google Scholar 

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Funding

SCP is supported by the National Institute on Alcohol Abuse and Alcoholism Grants UO1AA-019971, U24AA-024605 [Neurobiology of Adolescent Drinking in Adulthood (NADIA) project], RO1AA-010005, T32AA-026577, and P50AA-022538 (Center for Alcohol Research in Epigenetics), and by the Department of Veterans Affairs (VA Merit Grant I01 BX004517 & Senior Research Career Scientist Award). RSD is supported by the National Institute on Alcohol Abuse and Alcoholism NRSA training fellowship grant (F30AA-027936).

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  1. Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street (m/c 912), Chicago, IL, 60612, USA

    Russell S. Dulman, Gabriela M. Wandling & Subhash C. Pandey

  2. Jesse Brown Veterans Affairs Medical Center, 820 South Damen Avenue, Chicago, IL, 60612, USA

    Subhash C. Pandey

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  1. Russell S. Dulman
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  2. Gabriela M. Wandling
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Correspondence to Subhash C. Pandey.

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This article is part of the Topical Collection on The Pathobiology of Alcohol Consumption

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Dulman, R.S., Wandling, G.M. & Pandey, S.C. Epigenetic Mechanisms Underlying Pathobiology of Alcohol Use Disorder. Curr Pathobiol Rep 8, 61–73 (2020). https://doi.org/10.1007/s40139-020-00210-0

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