The epigenetic landscape of alcoholism.
- Authors
- Krishnan, Harish R; Sakharkar, Amul J; Teppen, Tara L; Berkel, Tiffani D M; Pandey, Subhash C
- Year
- 2014
- Journal
- International review of neurobiology
- PMID
- 25131543
- DOI
- 10.1016/B978-0-12-801311-3.00003-2
- PMCID
- PMC4337828
Alcoholism is a complex psychiatric disorder that has a multifactorial etiology. Epigenetic mechanisms are uniquely capable of accounting for the multifactorial nature of the disease in that they are highly stable and are affected by environmental factors, including alcohol itself. Chromatin remodeling causes changes in gene expression in specific brain regions contributing to the endophenotypes of alcoholism such as tolerance and dependence. The epigenetic mechanisms that regulate changes in gene expression observed in addictive behaviors respond not only to alcohol exposure but also to comorbid psychopathology such as the presence of anxiety and stress. This review summarizes recent developments in epigenetic research that may play a role in alcoholism. We propose that pharmacologically manipulating epigenetic targets, as demonstrated in various preclinical models, hold great therapeutic potential in the treatment and prevention of alcoholism.
Schematic representation of the epigenetic mechanisms of acetylation and methylation of lysine (K) residues at histone H3 and H4 tails that mediate the switching between ‘open’ (relaxed) and ‘closed’ (condensed) chromatin structures. Acetylation of histone H3 at K9, K14, K18 and K56 and of H4 at K5, K8, K12 and K16 are believed to relax the chromatin structure making it more accessible to transcription factors and chromatin remodelers, thereby promoting transcription, whereas methylation at these lysine residues condenses the chromatin followed by reduced gene transcription. Histone deacetylases (HDACs) remove acetyl groups and histone methyltransferases (HMTs) attach methyl groups at lysine residues. HDACs are classified into four different classes (class I–IV), of which the class III, sirtuins, are NAD+ dependent and comprise of seven different isoforms (SIRT 1–7). HDACs classes I (HDAC 1, 2, 3, and 8), II (HDAC 4–7, 9, and 10) and IV (HDAC11) are Zn+ dependent enzymes. Histone methyltransferases such as G9a, GLP and SETDB1 can catalyze the methylation of H3-K9 contributing to the restrictive state of the chromatin. Histone demethylases (HDMs) (e.g. KDM family) remove the methyl groups from lysine residues associated with repressive marks (e.g. H3K9) in the tails of histones facilitating the relaxation of chromatin. Histone acetyltransferases (HATs) such as GNAT and MYST families of enzymes and CREB-binding protein (CBP)-p300 complex transfer acetyl groups leading to relaxed chromatin (Allis et al., 2007; Kouzarides, 2007).
Schematic representation of the histone acetylation mechanisms in the amygdala of Sprague-Dawley (SD) and alcohol preferring (P) and –non-preferring (NP) rats, that are operative in the modulation of ethanol drinking and anxiety-like behaviors. Acute ethanol exposure of SD rats inhibits the histone deacetylase (HDAC) activity and increases CBP expression, which has intrinsic histone acetyltransferase activity, leading to the hyperacetylation of histones. This relaxes chromatin and increases expression of activity-regulated cytoskeleton-associated protein (Arc), brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY) resulting in acute ethanol’s anxiolytic effects. On the contrary, withdrawal from chronic ethanol treatment increases HDAC activity and decreases CBP levels leading to hypoacetylation of histones and a condensed state of chromatin that reduces BDNF, Arc and NPY, which precipitate anxiety-like behaviors. Treatment with trichostatin A (TSA), a pan-HDAC inhibitor, in alcohol-withdrawn SD rats was able to inhibit HDAC activity thereby increasing histone acetylation and expression of Arc, BDNF and NPY and further attenuated the withdrawal-related anxiety-like behaviors. Similarly, innately higher HDAC activity and HDAC2 expression in the amygdala of P rats compared to NP rats is associated with hypoacetylation of histones and low levels of Arc, BDNF and NPY and high levels of anxiety-like and alcohol-drinking behaviors. Inhibition of HDAC activity by treatment with TSA or knockdown of HDAC2 mRNA levels by using HDAC2 siRNA was able to correct the deficits in innate hypoacetylation and expression of Arc, BDNF and NPY thereby attenuating the high anxiety-like behavior and alcohol-preference in P rats (Pandey, Ugale et al., 2008; Moonat et al., 2013; You et al., 2014; Sakharkar, Zhang, et al., 2014).
Hypothetical representation of chromatin remodeling driven by histone acetylation mechanisms in the amygdala that may be operative in the process of alcohol addiction. The first drinking episode (comparable to an acute ethanol treatment in animal models) may cause more acetylation of the histone tails due to HDAC inhibition that results in an ‘open’ or relaxed chromatin structure leading to euphoric effects e.g. anxiolysis. Repeated exposure to alcohol (chronic drinking) may lead to neuroadaptive changes in these epigenetic mechanisms translating into the development of chronic tolerance to these euphoric effects of ethanol. Consequentially, cessation from drinking may precipitate withdrawal-related anxiety due to a rebound phenomenon and underlying epigenetic causes, e.g. hypoacetylation due to an increase in HDAC activity further ‘closing’ or condensing the chromatin structure, which manifests in the negative affective state or the ‘dark side of addiction’ (Koob & Le Moal, 2005). This leads to the development of dysphoric symptoms such as anxiety and depression and subjects tend to self-medicate with ethanol to relieve these dysphoric symptoms, resulting in alcohol abuse and dependence. As seen from preclinical data (Figure 2), this cycle of withdrawal leading to self-medication can be broken with HDAC inhibitors, which by promoting histone acetylation can revert a ‘closed’ chromatin structure to an ‘open’ configuration and can lead to a normal behavioral state (Pandey, Ugale et al., 2008; Arora et al., 2013; Pandey, Ugale, et al., 2008; You et al., 2014). Innately condensed chromatin due to higher HDAC2 expression and deficits in histone acetylation in the amygdala may also be involved in anxiety and alcoholism (Moonat et al., 2013; Sakharkar, Zhang, et al., 2014).
| # | Section | Preview |
|---|---|---|
| 0 | Introduction | Alcoholism can be characterized as a chronic relapsing brain disorder. The pathogenesis of… |
| 1 | Introduction | The comorbidity of anxiety and alcohol use disorders (AUD) is an important criterion to consider for… |
| 2 | Introduction | Both genetic and epigenetic (environment influenced) factors affect alcohol consumption and have… |
| 3 | Introduction | prompted researchers to classify it into a subfield called “Neuroepigenetics” (Day & Sweatt,… |
| 4 | Introduction | In addition to neuroplasticity, ethanol has been shown to affect epigenetic pathways in peripheral… |
| 5 | Introduction | This review will focus on two major forms of epigenetic regulation, histone covalent modifications… |
| 6 | Introduction — 1. Epigenetic Regulation due to Histone Covalent Modifications | Histone covalent modifications that have been identified as functionally important in regulating… |
| 7 | Introduction — 1. Epigenetic Regulation due to Histone Covalent Modifications | causes transcriptional repression (Allis et al., 2007). Histone covalent modifications are… |
| 8 | Introduction — 1. Epigenetic Regulation due to Histone Covalent Modifications — 1A. Role of Histone Acetylation and Deacetylation in Transcriptional Regulation | One of the well-characterized histone covalent modifications is lysine acetylation and its opposing… |
| 9 | Introduction — 1. Epigenetic Regulation due to Histone Covalent Modifications — 1A. Role of Histone Acetylation and Deacetylation in Transcriptional Regulation | CBP/p300 are an important family of HATs that act to remodel chromatin architecture functioning as… |
| 10 | Introduction — 1. Epigenetic Regulation due to Histone Covalent Modifications — 1A. Role of Histone Acetylation and Deacetylation in Transcriptional Regulation | neurodegenerative disorders (Valor, Viosca, Lopez-Atalaya, & Barco, 2013). Landmark studies have… |
| 11 | Introduction — 1. Epigenetic Regulation due to Histone Covalent Modifications — 1A. Role of Histone Acetylation and Deacetylation in Transcriptional Regulation | Generally, as discussed above, transcriptional activators and co-activators recruit HATs such as… |
| 12 | Introduction — 1. Epigenetic Regulation due to Histone Covalent Modifications — 1A. Role of Histone Acetylation and Deacetylation in Transcriptional Regulation | (Gräff et al., 2012, 2014). Inhibition of HDAC activity may serve as a useful pharmacological… |
| 13 | Introduction — 1. Epigenetic Regulation due to Histone Covalent Modifications — 1A. Role of Histone Acetylation and Deacetylation in Transcriptional Regulation | circadian pathways, could be an important avenue for therapeutic intervention. Recently, the sirtuin… |
| 14 | Introduction — 1. Epigenetic Regulation due to Histone Covalent Modifications — 1B. Alcohol and Histone Acetylation and Deacetylation Mechanisms in the Brain | CREB signaling pathways have been implicated in ethanol and other drugs of abuse phenotypes in both… |
| 15 | Introduction — 1. Epigenetic Regulation due to Histone Covalent Modifications — 1B. Alcohol and Histone Acetylation and Deacetylation Mechanisms in the Brain | anxiety-like behaviors (Pandey, Ugale, et al., 2008; Pandey, Zhang, et al., 2008) (Figure 2). The… |
| 16 | Introduction — 1. Epigenetic Regulation due to Histone Covalent Modifications — 1C. Role of HDACs in Alcoholism | Understanding the role played by HDACs in alcoholism and other drugs of abuse disorders is critical… |
| 17 | Introduction — 1. Epigenetic Regulation due to Histone Covalent Modifications — 1C. Role of HDACs in Alcoholism | deficits in BDNF-Arc signaling and dendritic spine density in the amygdala upon withdrawal from… |
| 18 | Introduction — 1. Epigenetic Regulation due to Histone Covalent Modifications — 1C. Role of HDACs in Alcoholism | compared with NP rats, which corresponded to lower H3K9 acetylation globally and specifically at the… |
| 19 | Introduction — 1. Epigenetic Regulation due to Histone Covalent Modifications — 1C. Role of HDACs in Alcoholism | regulate amygdaloid chromatin assembly, and alter the expression of genes implicated in alcohol… |
No entities extracted from this document yet.
No uploaded files.
In this knowledge base
| Title | Year | PMID |
|---|---|---|
| Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells? | 2018 | 29897633 |
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Elucidating Noradrenergic Neuroadaptations of the Central Amygdala in Alcohol Use Disorder. | Brodie MS | — | 2026 | → |
| SWI/SNF complexes modulate gene expression and the development of physical dependence to ethanol. | Mathies LD et al. | — | 2026 | → |
| Adolescent Binge Ethanol Exposure Confers Lasting Alcohol Tolerance across a Cumulative Ethanol Challenge in Adulthood: Involvement of Proinflammatory HMGB1 Signaling | Crews FT et al. | — | 2025 | — |
| Advancing translational exposomics: bridging genome, exposome and personalized medicine. | Sarigiannis D et al. | — | 2025 | → |
| Blood-based epigenome-wide association study and prediction of alcohol consumption. | Bernabeu E et al. | — | 2025 | → |
| Positive Selection in Aggression-Linked Genes and Their Protein Interaction Networks. | Awadi A et al. | — | 2025 | → |
| Chronic alcohol-induced long-lasting working memory deficits are associated with altered histone H3K9 dimethylation in the prefrontal cortex. | De Clerck M et al. | — | 2024 | → |
| Human genetics and epigenetics of alcohol use disorder. | Zhou H et al. | — | 2024 | → |
| Wonder symphony: epigenetics and the enchantment of the arts. | Gallazzi M et al. | — | 2024 | → |
| Adolescent binge ethanol impacts H3K36me3 regulation of synaptic genes. | Brocato ER et al. | — | 2023 | → |
| Effects of alcohol and PARP inhibition on RNA ribosomal engagement in cortical excitatory neurons. | Krishnan HR et al. | — | 2023 | → |
| Is DNA methylation in the brain a mechanism of alcohol use disorder? | Jarczak J et al. | — | 2023 | → |
| Post-translational modifications of histone and non-histone proteins in epigenetic regulation and translational applications in alcohol-associated liver disease: Challenges and research opportunities. | Rungratanawanich W et al. | — | 2023 | → |
| The Epigenetics of Migraine. | Zobdeh F et al. | — | 2023 | → |
| Current and Future Perspectives of Noncoding RNAs in Brain Function and Neuropsychiatric Disease. | Kyzar EJ et al. | — | 2022 | → |
| Promoter Specific Methylation of <i>SSTR4</i> is Associated With Alcohol Dependence in Han Chinese Males. | Zhao R et al. | — | 2022 | → |
| Sleep, sleep homeostasis and arousal disturbances in alcoholism. | Sharma R et al. | — | 2022 | → |
| The role of alcohol intake in the pharmacogenetics of treatment with clozapine. | Monroy-Jaramillo N et al. | — | 2022 | → |
| Unraveling the epigenomic and transcriptomic interplay during alcohol-induced anxiolysis. | Krishnan HR et al. | — | 2022 | → |
| Antisense-induced knockdown of cAMP response element-binding protein downregulates Per1 gene expression in the shell region of nucleus accumbens resulting in reduced alcohol consumption in mice. | Sharma R et al. | — | 2021 | → |
| Histone modifications, DNA methylation, and the epigenetic code of alcohol use disorder. | Bohnsack JP et al. | — | 2021 | → |
| Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition. | Bertels Z et al. | — | 2021 | → |
| Repeated Ethanol Exposure Alters DNA Methylation Status and Dynorphin/Kappa-Opioid Receptor Expression in Nucleus Accumbens of Alcohol-Preferring AA Rats. | Niinep K et al. | — | 2021 | → |
| Brain regional gene expression network analysis identifies unique interactions between chronic ethanol exposure and consumption. | Smith ML et al. | — | 2020 | → |
| Chronic alcohol exposure reduces acetylated histones in the sleep-wake regulatory brain regions to cause insomnia during withdrawal. | Sharma R et al. | — | 2020 | → |
| Epigenetic mechanisms underlying pathobiology of alcohol use disorder. | Dulman RS et al. | — | 2020 | → |
| Neuroimmune and epigenetic involvement in adolescent binge ethanol-induced loss of basal forebrain cholinergic neurons: Restoration with voluntary exercise. | Vetreno RP et al. | — | 2020 | → |
| Altered amygdala DNA methylation mechanisms after adolescent alcohol exposure contribute to adult anxiety and alcohol drinking. | Sakharkar AJ et al. | — | 2019 | → |
| Effect of Histone Deacetylase Inhibitor on Ethanol Withdrawal-Induced Hyperalgesia in Rats. | Pradhan AA et al. | — | 2019 | → |
| Epigenetics for the 21st-Century Biology Student. | Kang J et al. | — | 2019 | → |
| Essential Role of Histone Methyltransferase G9a in Rapid Tolerance to the Anxiolytic Effects of Ethanol. | Berkel TDM et al. | — | 2019 | → |
| How alcohol drinking affects our genes: an epigenetic point of view. | Ciafrè S et al. | — | 2019 | → |
| Long-term epigenetic changes in offspring mice exposed to alcohol during gestation and lactation. | Cantacorps L et al. | — | 2019 | → |
| Mechanisms of Persistent Neurobiological Changes Following Adolescent Alcohol Exposure: NADIA Consortium Findings. | Crews FT et al. | — | 2019 | → |
| The role of stress in drug addiction. An integrative review. | Ruisoto P et al. | — | 2019 | → |
| Adolescent alcohol exposure epigenetically regulates CREB signaling in the adult amygdala. | Zhang H et al. | — | 2018 | → |
| Associations Between MAOA-uVNTR Genotype, Maltreatment, MAOA Methylation, and Alcohol Consumption in Young Adult Males. | Bendre M et al. | — | 2018 | → |
| Association study of BDNF and DRD3 genes with alcohol use disorder in Schizophrenia. | Zai CC et al. | — | 2018 | → |
| Class I HDAC Inhibitors: Potential New Epigenetic Therapeutics for Alcohol Use Disorder (AUD). | Bourguet E et al. | — | 2018 | → |
| Donepezil Reverses Dendritic Spine Morphology Adaptations and Fmr1 Epigenetic Modifications in Hippocampus of Adult Rats After Adolescent Alcohol Exposure. | Mulholland PJ et al. | — | 2018 | → |
| Ethanol actions on the ventral tegmental area: novel potential targets on reward pathway neurons. | You C et al. | — | 2018 | → |
| Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells? | Prytkova I et al. | — | 2018 | → |
| Histone Deacetylase Inhibitor Suberanilohydroxamic Acid Treatment Reverses Hyposensitivity to γ-Aminobutyric Acid in the Ventral Tegmental Area During Ethanol Withdrawal. | You C et al. | — | 2018 | → |
| Neuroepigenetics of Neurotrophin Signaling: Neurobiology of Anxiety and Affective Disorders. | Règue-Guyon M et al. | — | 2018 | → |
| Role of the innate immune system in the neuropathological consequences induced by adolescent binge drinking. | Pascual M et al. | — | 2018 | → |
| Summary of the 2016 Alcohol and Immunology Research Interest Group (AIRIG) meeting. | Boule LA et al. | — | 2018 | → |
| Adolescent alcohol exposure alters lysine demethylase 1 (LSD1) expression and histone methylation in the amygdala during adulthood. | Kyzar EJ et al. | — | 2017 | → |
| Adolescent Alcohol Exposure-Induced Changes in Alpha-Melanocyte Stimulating Hormone and Neuropeptide Y Pathways via Histone Acetylation in the Brain During Adulthood. | Kokare DM et al. | — | 2017 | → |
| Alcohol effects on the epigenome in the germline: Role in the inheritance of alcohol-related pathology. | Chastain LG et al. | — | 2017 | → |
| Alcohol-Induced Behaviors Require a Subset of Drosophila JmjC-Domain Histone Demethylases in the Nervous System. | Pinzón JH et al. | — | 2017 | → |
| Alcohol-Induced Neuroadaptation Is Orchestrated by the Histone Acetyltransferase CBP. | Ghezzi A et al. | — | 2017 | → |
| Binge-Like Alcohol Exposure During Adolescence Disrupts Dopaminergic Neurotransmission in the Adult Prelimbic Cortex. | Trantham-Davidson H et al. | — | 2017 | → |
| Composite Agency: Semiotics of Modularity and Guiding Interactions. | Sharov AA | — | 2017 | → |
| Emerging Role of Epigenetic Mechanisms in Alcohol Addiction. | Berkel TD et al. | — | 2017 | → |
| Emerging roles for ncRNAs in alcohol use disorders. | Mayfield RD | — | 2017 | → |
| Epigenetic basis of the dark side of alcohol addiction. | Pandey SC et al. | — | 2017 | → |
| Epigenetic mechanisms of alcoholism and stress-related disorders. | Palmisano M et al. | — | 2017 | → |
| Genetic studies of alcohol dependence in the context of the addiction cycle. | Reilly MT et al. | — | 2017 | → |
| Adolescent Alcohol Exposure Persistently Impacts Adult Neurobiology and Behavior. | Crews FT et al. | — | 2016 | → |
| Alcohol Induces Parallel Changes in Hippocampal Histone H3 Phosphorylation and c-Fos Protein Expression in Male Rats. | McClain JA et al. | — | 2016 | → |
| A role for histone acetylation mechanisms in adolescent alcohol exposure-induced deficits in hippocampal brain-derived neurotrophic factor expression and neurogenesis markers in adulthood. | Sakharkar AJ et al. | — | 2016 | → |
| Cocaine and ethanol target 26S proteasome activity and gene expression in neuroblastoma cells. | Caputi FF et al. | — | 2016 | → |
| Molecular mechanisms underlying alcohol-drinking behaviours. | Ron D et al. | — | 2016 | → |
| Opioid gene expression changes and post-translational histone modifications at promoter regions in the rat nucleus accumbens after acute and repeated 3,4-methylenedioxy-methamphetamine (MDMA) exposure. | Caputi FF et al. | — | 2016 | → |
| Recent Advances in Nicotinic Receptor Signaling in Alcohol Abuse and Alcoholism. | Rahman S et al. | — | 2016 | → |
| Role of Growth Arrest and DNA Damage-Inducible, Beta in Alcohol-Drinking Behaviors. | Gavin DP et al. | — | 2016 | → |
| Targeted Epigenetic Modulation of Gene Expression in the Brain. | Kyzar EJ et al. | — | 2016 | → |
| The role of epigenetics in genetic and environmental epidemiology. | Ladd-Acosta C et al. | — | 2016 | → |
| Applying the new genomics to alcohol dependence. | Farris SP et al. | — | 2015 | → |
| "Boomerang Neuropathology" of Late-Onset Alzheimer's Disease is Shrouded in Harmful "BDDS": Breathing, Diet, Drinking, and Sleep During Aging. | Daulatzai MA | — | 2015 | → |
| Chronic Intermittent Ethanol Regulates Hippocampal GABA(A) Receptor Delta Subunit Gene Expression. | Follesa P et al. | — | 2015 | → |
| Commonalities and Distinctions Among Mechanisms of Addiction to Alcohol and Other Drugs. | Ozburn AR et al. | — | 2015 | → |
| Effects of acute ethanol exposure on class I HDACs family enzymes in wild-type and BDNF(+/-) mice. | Caputi FF et al. | — | 2015 | → |