1 6538 114 TRANSCRIPTIONAL REGULATORS AS TARGETS FOR ALCOHOL PHARMACOTHERAPIES. ALCOHOL USE DISORDER (AUD) IS A CHRONIC RELAPSING BRAIN DISEASE THAT CURRENTLY AFFLICTS OVER 15 MILLION ADULTS IN THE UNITED STATES. DESPITE ITS PREVALENCE, THERE ARE ONLY THREE FDA-APPROVED MEDICATIONS FOR AUD TREATMENT, ALL OF WHICH SHOW LIMITED EFFICACY. BECAUSE OF THEIR ABILITY TO ALTER EXPRESSION OF A LARGE NUMBER OF GENES, OFTEN WITH GREAT CELL-TYPE AND BRAIN-REGION SPECIFICITY, TRANSCRIPTION FACTORS AND EPIGENETIC MODIFIERS SERVE AS PROMISING NEW TARGETS FOR THE DEVELOPMENT OF AUD TREATMENTS AIMED AT THE NEURAL CIRCUITRY THAT UNDERLIES CHRONIC ALCOHOL ABUSE. IN THIS CHAPTER, WE WILL DISCUSS TRANSCRIPTIONAL REGULATORS THAT CAN BE TARGETED PHARMACOLOGICALLY AND HAVE SHOWN SOME EFFICACY IN ATTENUATING ALCOHOL CONSUMPTION WHEN TARGETED. SPECIFICALLY, THE TRANSCRIPTION FACTORS CYCLIC AMP-RESPONSIVE ELEMENT BINDING PROTEIN (CREB), PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARS), NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB), AND GLUCOCORTICOID RECEPTOR (GR), AS WELL AS THE EPIGENETIC ENZYMES, THE DNA METHYLTRANSFERASES (DNMTS) AND HISTONE DEACETYLASES (HDACS), WILL BE DISCUSSED. 2018 2 1870 31 EMERGING ROLE OF EPIGENETIC MECHANISMS IN ALCOHOL ADDICTION. ALCOHOL USE DISORDER (AUD) IS A COMPLEX BRAIN DISORDER WITH AN ARRAY OF PERSISTENT BEHAVIORAL AND NEUROCHEMICAL MANIFESTATIONS. BOTH GENETIC AND ENVIRONMENTAL FACTORS ARE KNOWN TO CONTRIBUTE TO THE DEVELOPMENT OF AUD, AND RECENT STUDIES ON ALCOHOL EXPOSURE AND SUBSEQUENT CHANGES IN GENE EXPRESSION SUGGEST THE IMPORTANCE OF EPIGENETIC MECHANISMS. IN PARTICULAR, HISTONE MODIFICATIONS AND DNA METHYLATION HAVE EMERGED AS IMPORTANT REGULATORS OF GENE EXPRESSION AND ASSOCIATED PHENOTYPES OF AUD. GIVEN THE THERAPEUTIC POTENTIAL OF EPIGENETIC TARGETS, THIS REVIEW AIMS TO SUMMARIZE THE ROLE OF EPIGENETIC REGULATION IN OUR CURRENT UNDERSTANDING OF AUD BY EVALUATING KNOWN EPIGENETIC SIGNATURES OF BRAIN REGIONS CRITICAL TO ADDICTIVE BEHAVIORS IN BOTH ANIMAL AND HUMAN STUDIES THROUGHOUT VARIOUS STAGES OF AUD. MORE SPECIFICALLY, THE EFFECTS OF ACUTE AND CHRONIC ALCOHOL EXPOSURE, TOLERANCE, AND POSTEXPOSURE WITHDRAWAL ON EPIGENETICALLY INDUCED CHANGES TO GENE EXPRESSION AND SYNAPTIC PLASTICITY WITHIN KEY BRAIN REGIONS AND THE ASSOCIATED BEHAVIORAL PHENOTYPES HAVE BEEN DISCUSSED. UNDERSTANDING THE CONTRIBUTION OF EPIGENETIC REGULATION TO CRUCIAL SIGNALING PATHWAYS MAY PROVE VITAL FOR FUTURE DEVELOPMENT OF NOVEL BIOMARKERS AND TREATMENT AGENTS IN AMELIORATING OR PREVENTING AUD. 2017 3 6517 31 TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS OF ADDICTION. INVESTIGATIONS OF LONG-TERM CHANGES IN BRAIN STRUCTURE AND FUNCTION THAT ACCOMPANY CHRONIC EXPOSURE TO DRUGS OF ABUSE SUGGEST THAT ALTERATIONS IN GENE REGULATION CONTRIBUTE SUBSTANTIALLY TO THE ADDICTIVE PHENOTYPE. HERE, WE REVIEW MULTIPLE MECHANISMS BY WHICH DRUGS ALTER THE TRANSCRIPTIONAL POTENTIAL OF GENES. THESE MECHANISMS RANGE FROM THE MOBILIZATION OR REPRESSION OF THE TRANSCRIPTIONAL MACHINERY - INCLUDING THE TRANSCRIPTION FACTORS DELTAFOSB, CYCLIC AMP-RESPONSIVE ELEMENT BINDING PROTEIN (CREB) AND NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) - TO EPIGENETICS - INCLUDING ALTERATIONS IN THE ACCESSIBILITY OF GENES WITHIN THEIR NATIVE CHROMATIN STRUCTURE INDUCED BY HISTONE TAIL MODIFICATIONS AND DNA METHYLATION, AND THE REGULATION OF GENE EXPRESSION BY NON-CODING RNAS. INCREASING EVIDENCE IMPLICATES THESE VARIOUS MECHANISMS OF GENE REGULATION IN THE LASTING CHANGES THAT DRUGS OF ABUSE INDUCE IN THE BRAIN, AND OFFERS NOVEL INROADS FOR ADDICTION THERAPY. 2011 4 6527 27 TRANSCRIPTIONAL CONTROL OF MALADAPTIVE AND PROTECTIVE RESPONSES IN ALCOHOLICS: A ROLE OF THE NF-KAPPAB SYSTEM. ALCOHOL DEPENDENCE AND ASSOCIATED COGNITIVE IMPAIRMENT APPEAR TO RESULT FROM MALADAPTIVE NEUROPLASTICITY IN RESPONSE TO CHRONIC ALCOHOL CONSUMPTION, NEUROINFLAMMATION AND NEURODEGENERATION. THE INHERENT STABILITY OF BEHAVIORAL ALTERATIONS ASSOCIATED WITH THE ADDICTED STATE SUGGESTS THAT TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS ARE OPERATIVE. NF-KAPPAB TRANSCRIPTION FACTORS ARE REGULATORS OF SYNAPTIC PLASTICITY AND INFLAMMATION, AND RESPONSIVE TO A VARIETY OF STIMULI INCLUDING ALCOHOL. THESE FACTORS ARE ABUNDANT IN THE BRAIN WHERE THEY HAVE DIVERSE FUNCTIONS THAT DEPEND ON THE COMPOSITION OF THE NF-KAPPAB COMPLEX AND CELLULAR CONTEXT. IN NEURON CELL BODIES, NF-KAPPAB IS CONSTITUTIVELY ACTIVE, AND INVOLVED IN NEURONAL INJURY AND NEUROPROTECTION. HOWEVER, AT THE SYNAPSE, NF-KAPPAB IS PRESENT IN A LATENT FORM AND UPON ACTIVATION IS TRANSPORTED TO THE CELL NUCLEUS. IN GLIA, NF-KAPPAB IS INDUCIBLE AND REGULATES INFLAMMATORY PROCESSES THAT EXACERBATE ALCOHOL-INDUCED NEURODEGENERATION. ANIMAL STUDIES DEMONSTRATE THAT ACUTE ALCOHOL EXPOSURE TRANSIENTLY ACTIVATES NF-KAPPAB, WHICH INDUCES NEUROINFLAMMATORY RESPONSES AND NEURODEGENERATION. POSTMORTEM STUDIES OF BRAINS OF HUMAN ALCOHOLICS SUGGEST THAT REPEATED CYCLES OF ALCOHOL CONSUMPTION AND WITHDRAWAL CAUSE ADAPTIVE CHANGES IN THE NF-KAPPAB SYSTEM THAT MAY PERMIT THE SYSTEM TO BETTER TOLERATE EXCESSIVE STIMULATION. THIS TYPE OF TOLERANCE, ENSURING A LOW DEGREE OF RESPONSIVENESS TO APPLIED STIMULI, APPARENTLY DIFFERS FROM THAT IN THE IMMUNE SYSTEM, AND MAY REPRESENT A COMPENSATORY RESPONSE THAT PROTECTS BRAIN CELLS AGAINST ALCOHOL NEUROTOXICITY. THIS VIEW IS SUPPORTED BY FINDINGS SHOWING PREFERENTIAL DOWNREGULATION OF PRO-APOPTOTIC GENE EXPRESSION IN THE AFFECTED BRAIN AREAS IN HUMAN ALCOHOLICS. ALTHOUGH FURTHER VERIFICATION IS NEEDED, WE SPECULATE THAT NF-KAPPAB-DRIVEN NEUROINFLAMMATION AND DISRUPTION TO NEUROPLASTICITY PLAY A SIGNIFICANT ROLE IN REGULATING ALCOHOL DEPENDENCE AND COGNITIVE IMPAIRMENT. 2011 5 2058 23 EPIGENETIC CONTROL OF GENE EXPRESSION IN THE ALCOHOLIC BRAIN. CHRONIC ALCOHOL EXPOSURE CAUSES WIDESPREAD CHANGES IN BRAIN GENE EXPRESSION IN HUMANS AND ANIMAL MODELS. MANY OF THESE CONTRIBUTE TO CELLULAR ADAPTATIONS THAT ULTIMATELY LEAD TO BEHAVIORAL TOLERANCE AND ALCOHOL DEPENDENCE. THERE IS AN EMERGING APPRECIATION FOR THE ROLE OF EPIGENETIC PROCESSES IN ALCOHOL-INDUCED CHANGES IN BRAIN GENE EXPRESSION AND BEHAVIOR. FOR EXAMPLE, CHRONIC ALCOHOL EXPOSURE PRODUCES CHANGES IN DNA AND HISTONE METHYLATION, HISTONE ACETYLATION, AND MICRORNA EXPRESSION THAT AFFECT EXPRESSION OF MULTIPLE GENES IN VARIOUS TYPES OF BRAIN CELLS (I.E., NEURONS AND GLIA) AND CONTRIBUTE TO BRAIN PATHOLOGY AND BRAIN PLASTICITY ASSOCIATED WITH ALCOHOL ABUSE AND DEPENDENCE. DRUGS TARGETING THE EPIGENETIC "MASTER REGULATORS" ARE EMERGING AS POTENTIAL THERAPEUTICS FOR NEURODEGENERATIVE DISORDERS AND DRUG ADDICTION. 2013 6 3398 28 HOW ALCOHOL DRINKING AFFECTS OUR GENES: AN EPIGENETIC POINT OF VIEW. THIS WORK HIGHLIGHTS RECENT STUDIES IN EPIGENETIC MECHANISMS THAT PLAY A ROLE IN ALCOHOLISM, WHICH IS A COMPLEX MULTIFACTORIAL DISORDER. THERE IS A LARGE BODY OF EVIDENCE SHOWING THAT ALCOHOL CAN MODIFY GENE EXPRESSION THROUGH EPIGENETIC PROCESSES, NAMELY DNA METHYLATION AND NUCLEOSOMAL REMODELING VIA HISTONE MODIFICATIONS. IN THAT REGARD, CHRONIC EXPOSURE TO ETHANOL MODIFIES DNA AND HISTONE METHYLATION, HISTONE ACETYLATION, AND MICRORNA EXPRESSION. THE ALCOHOL-MEDIATED CHROMATIN REMODELING IN THE BRAIN PROMOTES THE TRANSITION FROM USE TO ABUSE AND ADDICTION. UNRAVELLING THE MULTIPLEX PATTERN OF MOLECULAR MODIFICATIONS INDUCED BY ETHANOL COULD SUPPORT THE DEVELOPMENT OF NEW THERAPIES FOR ALCOHOLISM AND DRUG ADDICTION TARGETING EPIGENETIC PROCESSES. 2019 7 2606 36 EPIGENETICS-BEYOND THE GENOME IN ALCOHOLISM. GENETIC AND ENVIRONMENTAL FACTORS PLAY A ROLE IN THE DEVELOPMENT OF ALCOHOLISM. WHOLE-GENOME EXPRESSION PROFILING HAS HIGHLIGHTED THE IMPORTANCE OF SEVERAL GENES THAT MAY CONTRIBUTE TO ALCOHOL ABUSE DISORDERS. IN ADDITION, MORE RECENT FINDINGS HAVE ADDED YET ANOTHER LAYER OF COMPLEXITY TO THE OVERALL MOLECULAR MECHANISMS INVOLVED IN A PREDISPOSITION TO ALCOHOLISM AND ADDICTION BY DEMONSTRATING THAT PROCESSES RELATED TO GENETIC FACTORS THAT DO NOT MANIFEST AS DNA SEQUENCE CHANGES (I.E., EPIGENETIC PROCESSES) PLAY A ROLE. BOTH ACUTE AND CHRONIC ETHANOL EXPOSURE CAN ALTER GENE EXPRESSION LEVELS IN SPECIFIC NEURONAL CIRCUITS THAT GOVERN THE BEHAVIORAL CONSEQUENCES RELATED TO TOLERANCE AND DEPENDENCE. THE UNREMITTING CYCLE OF ALCOHOL CONSUMPTION OFTEN INCLUDES SATIATION AND SELF-MEDICATION WITH ALCOHOL, FOLLOWED BY EXCRUCIATING WITHDRAWAL SYMPTOMS AND THE RESULTANT RELAPSE, WHICH REFLECTS BOTH THE POSITIVE AND NEGATIVE AFFECTIVE STATES OF ALCOHOL ADDICTION. RECENT STUDIES HAVE INDICATED THAT BEHAVIORAL CHANGES INDUCED BY ACUTE AND CHRONIC ETHANOL EXPOSURE MAY INVOLVE CHROMATIN REMODELING RESULTING FROM COVALENT HISTONE MODIFICATIONS AND DNA METHYLATION IN THE NEURONAL CIRCUITS INVOLVING A BRAIN REGION CALLED THE AMYGDALA. THESE FINDINGS HAVE HELPED IDENTIFY ENZYMES INVOLVED IN EPIGENETIC MECHANISMS, SUCH AS THE HISTONE DEACETYLASE, HISTONE ACETYLTRANSFERASE, AND DNA METHYLTRANSFERASE ENZYMES, AS NOVEL THERAPEUTIC TARGETS FOR THE DEVELOPMENT OF FUTURE PHARMACOTHERAPIES FOR THE TREATMENT OF ALCOHOLISM. 2012 8 2250 30 EPIGENETIC MODULATION OF OPIOID RECEPTORS BY DRUGS OF ABUSE. CHRONIC EXPOSURE TO DRUGS OF ABUSE PRODUCES PROFOUND CHANGES IN GENE EXPRESSION AND NEURAL ACTIVITY ASSOCIATED WITH DRUG-SEEKING AND TAKING BEHAVIOR. DYSREGULATION OF OPIOID RECEPTOR GENE EXPRESSION IS COMMONLY OBSERVED ACROSS A VARIETY OF ABUSED SUBSTANCES INCLUDING OPIOIDS, COCAINE, AND ALCOHOL. EARLY STUDIES IN CULTURED CELLS SHOWED THAT THE SPATIAL AND TEMPORAL GENE EXPRESSION OF OPIOID RECEPTORS ARE REGULATED BY EPIGENETIC MECHANISMS INCLUDING DNA AND HISTONE MODIFICATIONS AND NON-CODING RNAS. ACCUMULATING EVIDENCE INDICATE THAT DRUGS OF ABUSE CAN MODULATE OPIOID RECEPTOR GENE EXPRESSION BY TARGETING VARIOUS EPIGENETIC REGULATORY NETWORKS. BASED ON CURRENT CELLULAR AND ANIMAL MODELS OF SUBSTANCE USE DISORDER AND CLINICAL EVIDENCE, THIS REVIEW SUMMARIZES HOW CHRONIC DRUG EXPOSURE ALTERS THE GENE EXPRESSION OF MU, DELTA, KAPPA, AND NOCICEPTIN RECEPTORS VIA DNA AND HISTONE MODIFICATIONS. THE INFLUENCE OF DRUGS OF ABUSE ON EPIGENETIC MODULATORS, SUCH AS NON-CODING RNAS AND TRANSCRIPTION FACTORS, IS ALSO PRESENTED. FINALLY, THE THERAPEUTIC POTENTIAL OF MANIPULATING EPIGENETIC PROCESSES AS AN AVENUE TO TREAT SUBSTANCE USE DISORDER IS DISCUSSED. 2022 9 3376 27 HISTONE-MEDIATED EPIGENETICS IN ADDICTION. MANY OF THE BRAIN REGIONS, NEUROTRANSMITTER SYSTEMS, AND BEHAVIORAL CHANGES THAT OCCUR AFTER OCCASIONAL DRUG USE IN HEALTHY SUBJECTS AND AFTER CHRONIC DRUG ABUSE IN ADDICTED PATIENTS ARE WELL CHARACTERIZED. AN EMERGING LITERATURE SUGGESTS THAT EPIGENETIC PROCESSES, THOSE PROCESSES THAT REGULATE THE ACCESSIBILITY OF DNA TO REGULATORY PROTEINS WITHIN THE NUCLEUS, ARE KEYS TO HOW ADDICTION DEVELOPS AND HOW IT MAY BE TREATED. INVESTIGATIONS OF THE REGULATION OF CHROMATIN, THE ORGANIZATIONAL SYSTEM OF DNA, BY HISTONE MODIFICATION ARE LEADING TO A NEW UNDERSTANDING OF THE CELLULAR AND BEHAVIORAL ALTERATIONS THAT OCCUR AFTER DRUG USE. WE WILL DESCRIBE HOW, WHEN, AND WHERE HISTONE TAILS ARE MODIFIED AND HOW SOME OF THE MOST RECOGNIZED HISTONE REGULATION PATTERNS ARE INVOLVED IN THE CYCLE OF ADDICTION, INCLUDING INITIAL AND CHRONIC DRUG INTAKE, WITHDRAWAL, ABSTINENCE, AND RELAPSE. FINALLY, WE CONSIDER HOW AN APPROACH THAT TARGETS HISTONE MODIFICATIONS MAY PROMOTE SUCCESSFUL TREATMENT. 2014 10 6324 29 THE ROLE OF ALPHA-SYNUCLEIN IN THE PATHOPHYSIOLOGY OF ALCOHOLISM. ALCOHOLISM HAS COMPLEX ETIOLOGY AND THERE IS EVIDENCE FOR BOTH GENETIC AND ENVIRONMENTAL FACTORS IN ITS PATHOPHYSIOLOGY. CHRONIC, LONG-TERM ALCOHOL ABUSE AND ALCOHOL DEPENDENCE ARE ASSOCIATED WITH NEURONAL LOSS WITH THE PREFRONTAL CORTEX BEING PARTICULARLY SUSCEPTIBLE TO NEUROTOXIC DAMAGE. THIS BRAIN REGION IS INVOLVED IN THE DEVELOPMENT AND PERSISTENCE OF ALCOHOL ADDICTION AND NEUROTOXIC DAMAGE IS LIKELY TO EXACERBATE THE REINFORCING EFFECTS OF ALCOHOL AND MAY HINDER TREATMENT. UNDERSTANDING THE MECHANISM OF ALCOHOL'S NEUROTOXIC EFFECTS ON THE BRAIN AND THE GENETIC RISK FACTORS ASSOCIATED WITH ALCOHOL ABUSE ARE THE FOCUS OF CURRENT RESEARCH. BECAUSE OF ITS WELL-ESTABLISHED ROLE IN NEURODEGENERATIVE AND NEUROPSYCHOLOGICAL DISORDERS, AND ITS EMERGING ROLE IN THE PATHOPHYSIOLOGY OF ADDICTION, HERE WE REVIEW THE GENETIC AND EPIGENETIC FACTORS INVOLVED IN REGULATING ALPHA-SYNUCLEIN EXPRESSION AND ITS POTENTIAL ROLE IN THE PATHOPHYSIOLOGY OF CHRONIC ALCOHOL ABUSE. ELUCIDATION OF THE MECHANISMS OF ALPHA-SYNUCLEIN REGULATION MAY PROVE BENEFICIAL IN UNDERSTANDING THE ROLE OF THIS KEY SYNAPTIC PROTEIN IN DISEASE AND ITS POTENTIAL FOR THERAPEUTIC MODULATION IN THE TREATMENT OF SUBSTANCE USE DISORDERS AS WELL AS OTHER NEURODEGENERATIVE DISEASES. 2013 11 6775 29 [ALCOHOL DEPENDENCE MEDIATED BY MONOAMINE NEUROTRANSMITTERS IN THE CENTRAL NERVOUS SYSTEM]. ALCOHOL DEPENDENCE, A CHRONIC RELAPSING BRAIN DISEASE WITH THE CHARACTERISTICS OF DRINKING ALCOHOL OUT OF CONTROL, HAS BECOME A SERIOUS SOCIAL PROBLEM. MONOAMINE NEUROTRANSMITTERS, MAINLY INCLUDING DOPAMINE AND 5-HYDROXYTRYP NOTTAMINE, PLAY IMPORTANT ROLES IN THE OCCURRENCE, DEVELOPMENT AND NEURAL DYSFUNCTION OF ALCOHOL DEPENDENCE SYNDROME. IN THIS REVIEW, THE ROLES OF KEY FACTORS OF THE MONOAMINE SYSTEM (DOPAMINE RECEPTOR GENES, 5-HYDROXYTRYPTAMINE RECEPTOR GENES, TRANSPORTER GENES, TYROSINE HYDROXYLASE GENE, TRYPTOPHANHYDROXYLASE GENE AND MONOAMINE OXIDASE GENE) IN ALCOHOL DEPENDENCE WERE DISCUSSED, AND STRATEGIES FOR FURTHER STUDIES OF MOLECULAR MECHANISMS WERE PROPOSED BASED ON GENE KNOCKOUT MICE MODELS GENERATED IN OUR LABORATORY. THEN, COMBINING WITH STUDIES ON TYROSINE HYDROXYLASE ACTIVATOR CAMKII IN OUR LAB, THERAPEUTIC TARGETS WERE DISCUSSED. BESIDES, EPIGENETIC STRATEGIES FOR PREVENTION AND TREATMENT OF ALCOHOL DEPENDENCE SYNDROME WERE PROPOSED. FURTHERMORE, MANIPULATING METHYLATION LEVELS IN GENE REGULATORY REGIONS AND ALTERNATIVE SPLICING OF PRE-MRNAS MIGHT ALSO HAVE CLINICAL IMPLICATIONS. FINALLY, BASED ON NEW FINDINGS ON GENETIC POLYMORPHISM, IT IS OF GREAT POTENTIAL TO CARRY OUT INDIVIDUAL PREVENTION AND TREATMENT FOR PATIENTS SUFFERING FROM ALCOHOL DEPENDENCE. 2014 12 1623 43 DNA MODIFICATIONS IN MODELS OF ALCOHOL USE DISORDERS. CHRONIC ALCOHOL USE AND ABUSE RESULT IN WIDESPREAD CHANGES TO GENE EXPRESSION, SOME OF WHICH CONTRIBUTE TO THE DEVELOPMENT OF ALCOHOL-USE DISORDERS (AUD). GENE EXPRESSION IS CONTROLLED, IN PART, BY A GROUP OF REGULATORY SYSTEMS OFTEN REFERRED TO AS EPIGENETIC FACTORS, WHICH INCLUDES, AMONG OTHER MECHANISMS, CHEMICAL MARKS MADE ON THE HISTONE PROTEINS AROUND WHICH GENOMIC DNA IS WOUND TO FORM CHROMATIN, AND ON NUCLEOTIDES OF THE DNA ITSELF. IN PARTICULAR, ALCOHOL HAS BEEN SHOWN TO PERTURB THE EPIGENETIC MACHINERY, LEADING TO CHANGES IN GENE EXPRESSION AND CELLULAR FUNCTIONS CHARACTERISTIC OF AUD AND, ULTIMATELY, TO ALTERED BEHAVIOR. DNA MODIFICATIONS IN PARTICULAR ARE SEEING INCREASING RESEARCH IN THE CONTEXT OF ALCOHOL USE AND ABUSE. TO DATE, STUDIES OF DNA MODIFICATIONS IN AUD HAVE PRIMARILY LOOKED AT GLOBAL METHYLATION PROFILES IN HUMAN BRAIN AND BLOOD, GENE-SPECIFIC METHYLATION PROFILES IN ANIMAL MODELS, METHYLATION CHANGES ASSOCIATED WITH PRENATAL ETHANOL EXPOSURE, AND THE POTENTIAL THERAPEUTIC ABILITIES OF DNA METHYLTRANSFERASE INHIBITORS. FUTURE STUDIES MAY BE AIMED AT IDENTIFYING CHANGES TO MORE RECENTLY DISCOVERED DNA MODIFICATIONS, UTILIZING NEW METHODS TO DISCRIMINATE METHYLATION PROFILES BETWEEN CELL TYPES, THUS CLARIFYING HOW ALCOHOL INFLUENCES THE METHYLOMES OF CELL-TYPE POPULATIONS AND HOW THIS MAY AFFECT DOWNSTREAM PROCESSES. THESE STUDIES AND MORE IN-DEPTH PROBING OF DNA METHYLATION WILL BE KEY TO DETERMINING WHETHER DNA-LEVEL EPIGENETIC REGULATION PLAYS A CAUSATIVE ROLE IN AUD AND CAN THUS BE TARGETED FOR TREATMENT OF THE DISORDER. 2017 13 6257 25 THE MOLECULAR BASIS OF TOLERANCE. TOLERANCE IS DEFINED AS THE DIMINISHED RESPONSE TO ALCOHOL OR OTHER DRUGS OVER THE COURSE OF REPEATED OR PROLONGED EXPOSURE. THIS MECHANISM ALLOWS PHYSIOLOGICAL PROCESSES TO ACHIEVE STABILITY IN A CONSTANTLY CHANGING ENVIRONMENT. THE ONSET OF TOLERANCE MAY OCCUR WITHIN MINUTES, DURING A SINGLE EXPOSURE TO ALCOHOL (I.E., ACUTE TOLERANCE), OR OVER LONGER TIMEFRAMES AND WITH PROLONGED EXPOSURE TO ALCOHOL (I.E., RAPID OR CHRONIC TOLERANCE). CHANGES IN TOLERANCE INDUCED BY ALCOHOL MAY AFFECT SEVERAL PROCESSES AT THE MOLECULAR, CELLULAR, OR BEHAVIORAL LEVEL. THESE EFFECTS OFTEN ARE INTERRELATED AND MAY BE DIFFICULT TO SEPARATE. THIS ARTICLE DESCRIBES CHANGES AT THE MOLECULAR LEVEL THAT ARE RELATED TO THE ONSET OF ACUTE, RAPID, OR CHRONIC TOLERANCE. IT FOCUSES ON NEURONAL MEMBRANE-BOUND CHANNELS AND THE FACTORS THAT AFFECT THEIR FUNCTION AND PRODUCTION, SUCH AS MODIFICATION OF PROTEIN SYNTHESIS AND ACTIVITY, INTERACTION WITH THE MEMBRANE LIPID MICROENVIRONMENT, EPIGENETIC EFFECTS ON CYTOPLASMIC REGULATION, AND GENE TRANSCRIPTION. ALSO CONSIDERED IS THE GENETICS OF TOLERANCE. 2008 14 2013 40 EPIGENETIC BASIS OF THE DARK SIDE OF ALCOHOL ADDICTION. ALCOHOLISM IS A COMPLEX BRAIN DISEASE CHARACTERIZED BY THREE DISTINCT STAGES OF THE ADDICTION CYCLE THAT MANIFEST AS NEUROADAPTIVE CHANGES IN THE BRAIN. ONE SUCH STAGE OF THE ADDICTION CYCLE IS ALCOHOL WITHDRAWAL AND THE NEGATIVE AFFECTIVE STATES THAT PROMOTE DRINKING AND MAINTAIN ADDICTION. REPEATED ALCOHOL USE, GENETIC PREDISPOSITION TO ALCOHOLISM AND ANXIETY, AND ALCOHOL EXPOSURE DURING CRUCIAL DEVELOPMENTAL PERIODS ALL CONTRIBUTE TO THE DEVELOPMENT OF ALCOHOL-INDUCED WITHDRAWAL AND NEGATIVE AFFECTIVE SYMPTOMS. EPIGENETIC MODIFICATIONS WITHIN THE AMYGDALA HAVE PROVIDED A MOLECULAR BASIS OF THESE NEGATIVE AFFECTIVE SYMPTOMS, ALSO KNOWN AS THE DARK SIDE OF ADDICTION. HERE, WE PROPOSE THAT ALLOSTATIC CHANGE WITHIN THE EPIGENOME IN THE AMYGDALA IS A PRIME MECHANISM OF THE BIOLOGICAL BASIS OF NEGATIVE AFFECTIVE STATES RESULTING FROM, AND CONTRIBUTING TO, ALCOHOLISM. ACUTE ALCOHOL EXPOSURE PRODUCES AN ANXIOLYTIC RESPONSE WHICH IS ASSOCIATED WITH THE OPENING OF CHROMATIN DUE TO INCREASED HISTONE ACETYLATION, INCREASED CREB BINDING PROTEIN (CBP) LEVELS, AND HISTONE DEACETYLASE (HDAC) INHIBITION. AFTER CHRONIC ETHANOL EXPOSURE, THESE CHANGES RETURN TO BASELINE ALONG WITH ANXIETY-LIKE BEHAVIORS. HOWEVER, DURING WITHDRAWAL, HISTONE ACETYLATION DECREASES DUE TO INCREASED HDAC ACTIVITY AND DECREASED CBP LEVELS IN THE AMYGDALA CIRCUITRY LEADING TO THE DEVELOPMENT OF ANXIETY-LIKE BEHAVIORS. ADDITIONALLY, INNATELY HIGHER EXPRESSION OF THE HDAC2 ISOFORM LEADS TO A DEFICIT IN GLOBAL AND GENE-SPECIFIC HISTONE ACETYLATION IN THE AMYGDALA THAT IS ASSOCIATED WITH A DECREASE IN THE EXPRESSION OF SEVERAL SYNAPTIC PLASTICITY-ASSOCIATED GENES AND MAINTAINING HEIGHTENED ANXIETY-LIKE BEHAVIOR AND EXCESSIVE ALCOHOL INTAKE. ADOLESCENT ALCOHOL EXPOSURE ALSO LEADS TO HIGHER EXPRESSION OF HDAC2 AND A DEFICIT IN HISTONE ACETYLATION LEADING TO DECREASED EXPRESSION OF SYNAPTIC PLASTICITY-ASSOCIATED GENES AND HIGH ANXIETY AND DRINKING BEHAVIOR IN ADULTHOOD. ALL THESE STUDIES INDICATE THAT THE EPIGENOME CAN UNDERGO ALLOSTATIC REPROGRAMMING IN THE AMYGDALOID CIRCUITRY DURING VARIOUS STAGES OF ALCOHOL EXPOSURE. FURTHERMORE, OPENING THE CHROMATIN BY INHIBITING HDACS USING PHARMACOLOGICAL OR GENETIC MANIPULATIONS CAN LEAD TO THE ATTENUATION OF ANXIETY AS WELL AS ALCOHOL INTAKE. CHROMATIN REMODELING PROVIDES A CLEAR BIOLOGICAL BASIS FOR THE NEGATIVE AFFECTIVE STATES SEEN DURING ALCOHOL ADDICTION AND PRESENTS OPPORTUNITIES FOR NOVEL DRUG DEVELOPMENT AND TREATMENT OPTIONS. THIS ARTICLE IS PART OF THE SPECIAL ISSUE ENTITLED "ALCOHOLISM". 2017 15 2598 28 EPIGENETICS OF THE DEPRESSED BRAIN: ROLE OF HISTONE ACETYLATION AND METHYLATION. MAJOR DEPRESSIVE DISORDER IS A CHRONIC, REMITTING SYNDROME INVOLVING WIDELY DISTRIBUTED CIRCUITS IN THE BRAIN. STABLE ALTERATIONS IN GENE EXPRESSION THAT CONTRIBUTE TO STRUCTURAL AND FUNCTIONAL CHANGES IN MULTIPLE BRAIN REGIONS ARE IMPLICATED IN THE HETEROGENEITY AND PATHOGENESIS OF THE ILLNESS. EPIGENETIC EVENTS THAT ALTER CHROMATIN STRUCTURE TO REGULATE PROGRAMS OF GENE EXPRESSION HAVE BEEN ASSOCIATED WITH DEPRESSION-RELATED BEHAVIOR, ANTIDEPRESSANT ACTION, AND RESISTANCE TO DEPRESSION OR 'RESILIENCE' IN ANIMAL MODELS, WITH INCREASING EVIDENCE FOR SIMILAR MECHANISMS OCCURRING IN POSTMORTEM BRAINS OF DEPRESSED HUMANS. IN THIS REVIEW, WE DISCUSS RECENT ADVANCES IN OUR UNDERSTANDING OF EPIGENETIC CONTRIBUTIONS TO DEPRESSION, IN PARTICULAR THE ROLE OF HISTONE ACETYLATION AND METHYLATION, WHICH ARE REVEALING NOVEL MECHANISTIC INSIGHT INTO THE SYNDROME THAT MAY AID IN THE DEVELOPMENT OF NOVEL TARGETS FOR DEPRESSION TREATMENT. 2013 16 834 26 CHEMICAL BIOLOGY OF LYSINE DEMETHYLASES. ABNORMAL LEVELS OF DNA METHYLATION AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. METHYLATION OF LYSINES WITHIN HISTONE TAILS IS A KEY MODIFICATION THAT CONTRIBUTES TO INCREASED GENE EXPRESSION OR REPRESSION DEPENDING ON THE SPECIFIC RESIDUE AND DEGREE OF METHYLATION, WHICH IS IN TURN CONTROLLED BY THE INTERPLAY OF LYSINE METHYL TRANSFERASES AND DEMETHYLASES. DRUGS THAT TARGET THESE AND OTHER ENZYMES CONTROLLING CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS ACTING ON DOWNSTREAM BIOCHEMICAL PATHWAYS THAT ARE SUSCEPTIBLE TO DEGENERACY. LYSINE DEMETHYLASES, FIRST DISCOVERED IN 2004, ARE THE SUBJECT OF INCREASING INTEREST AS THERAPEUTIC TARGETS. THIS REVIEW PROVIDES AN OVERVIEW OF RECENT FINDINGS IMPLICATING LYSINE DEMETHYLASES IN A RANGE OF THERAPEUTIC AREAS INCLUDING ONCOLOGY, IMMUNOINFLAMMATION, METABOLIC DISORDERS, NEUROSCIENCE, VIROLOGY AND REGENERATIVE MEDICINE, TOGETHER WITH A SUMMARY OF RECENT ADVANCES IN STRUCTURAL BIOLOGY AND SMALL MOLECULE INHIBITOR DISCOVERY, SUPPORTING THE TRACTABILITY OF THE PROTEIN FAMILY FOR THE DEVELOPMENT OF SELECTIVE DRUGLIKE INHIBITORS. 2011 17 4768 27 NUCLEAR EFFECTS OF ETHANOL-INDUCED PROTEASOME INHIBITION IN LIVER CELLS. ALCOHOL INGESTION CAUSES ALTERATION IN SEVERAL CELLULAR MECHANISMS, AND LEADS TO INFLAMMATION, APOPTOSIS, IMMUNOLOGICAL RESPONSE DEFECTS, AND FIBROSIS. THESE PHENOMENA ARE ASSOCIATED WITH SIGNIFICANT CHANGES IN THE EPIGENETIC MECHANISMS, AND SUBSEQUENTLY, TO LIVER CELL MEMORY. THE UBIQUITIN-PROTEASOME PATHWAY IS ONE OF THE VITAL PATHWAYS IN THE CELL THAT BECOMES DYSFUNCTIONAL AS A RESULT OF CHRONIC ETHANOL CONSUMPTION. INHIBITION OF THE PROTEASOME ACTIVITY IN THE NUCLEUS CAUSES CHANGES IN THE TURNOVER OF TRANSCRIPTIONAL FACTORS, HISTONE MODIFYING ENZYMES, AND THEREFORE, AFFECTS EPIGENETIC MECHANISMS. ALCOHOL CONSUMPTION HAS BEEN ASSOCIATED WITH AN INCREASE IN HISTONE ACETYLATION AND A DECREASE IN HISTONE METHYLATION, WHICH LEADS TO GENE EXPRESSION CHANGES. DNA AND HISTONE MODIFICATIONS THAT RESULT FROM ETHANOL-INDUCED PROTEASOME INHIBITION ARE KEY PLAYERS IN REGULATING GENE EXPRESSION, ESPECIALLY GENES INVOLVED IN THE CELL CYCLE, IMMUNOLOGICAL RESPONSES, AND METABOLISM OF ETHANOL. THE PRESENT REVIEW HIGHLIGHTS THE CONSEQUENCES OF ETHANOL-INDUCED PROTEASOME INHIBITION IN THE NUCLEUS OF LIVER CELLS THAT ARE CHRONICALLY EXPOSED TO ETHANOL. 2009 18 2194 35 EPIGENETIC MODIFICATION IN NEUROPATHIC PAIN. NEUROPATHIC PAIN IS CHARACTERIZED BY COMPLICATED COMBINATION OF POSITIVE (E.G., HYPERALGESIA AND ALLODYNIA) AND NEGATIVE (E.G., HYPOESTHESIA AND HYPOALGESIA) SYMPTOMS, AND IS OFTEN REFRACTORY TO CONVENTIONAL PHARMACOLOGICAL AGENTS, INCLUDING MORPHINE. ALTHOUGH THE MOLECULAR MECHANISMS FOR POSITIVE SYMPTOMS ARE EXTENSIVELY STUDIED, THOSE FOR NEGATIVE SYMPTOMS ARE POORLY UNDERSTOOD. THERE IS CONVINCING EVIDENCE THAT ALTERED GENE EXPRESSION WITHIN PERIPHERAL AND CENTRAL NERVOUS SYSTEMS IS A KEY MECHANISM FOR NEUROPATHIC PAIN; HOWEVER, ITS TRANSCRIPTIONAL MECHANISMS ARE POORLY UNDERSTOOD. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS (E.G., ACETYLATION, METHYLATION, AND PHOSPHORYLATION), ARE KNOWN TO CAUSE STABLE GENE EXPRESSION VIA CHROMATIN REMODELING. THESE MECHANISMS HAVE A ROLE NOT ONLY IN THE DETERMINATION OF DEVELOPMENTAL CELL FATES, BUT ALSO IN THE PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES IN NERVOUS SYSTEM. MOREOVER, EPIGENETIC THERAPIES USING EPIGENETIC MODIFYING COMPOUNDS ARE PROGRESSIVELY ADVANCED IN THE TREATMENTS OF DIVERSE DISEASES, INCLUDING CANCER AND NEUROLOGICAL DISEASES. IMPORTANTLY, THERE IS EMERGING EVIDENCE THAT A VARIETY OF GENES UNDERGO EPIGENETIC REGULATION VIA DNA METHYLATION AND HISTONE MODIFICATIONS WITHIN PERIPHERAL AND CENTRAL NERVOUS SYSTEMS, THEREBY CONTRIBUTING TO THE ALTERATIONS IN BOTH PAIN SENSITIVITY AND PHARMACOLOGICAL EFFICACY IN NEUROPATHIC PAIN. IN THIS REVIEW, WE WILL HIGHLIGHT THE EPIGENETIC GENE REGULATION UNDERLYING NEUROPATHIC PAIN, ESPECIALLY FOCUSING ON THE NEGATIVE SYMPTOMS. MOREOVER, WE WILL DISCUSS WHETHER EPIGENETIC MECHANISMS CAN SERVE AS A POTENTIAL TARGET TO TREAT NEUROPATHIC PAIN. 2015 19 1796 35 EFFECT OF GERM-FREE STATUS ON TRANSCRIPTIONAL PROFILES IN THE NUCLEUS ACCUMBENS AND TRANSCRIPTOMIC RESPONSE TO CHRONIC MORPHINE. OPIOID USE DISORDER IS A PUBLIC HEALTH CRISIS THAT CAUSES TREMENDOUS SUFFERING FOR PATIENTS AS WELL AS SUBSTANTIAL SOCIAL AND ECONOMIC COSTS FOR SOCIETY. THERE ARE CURRENTLY AVAILABLE TREATMENTS FOR PATIENTS WITH OPIOID USE DISORDER, BUT THEY REMAIN INTOLERABLE OR INEFFECTIVE FOR MANY. THUS THE NEED TO DEVELOP NEW AVENUES FOR THERAPEUTICS DEVELOPMENT IN THIS SPACE IS GREAT. SUBSTANTIAL WORK IN MODELS OF SUBSTANCE USE DISORDERS, INCLUDING OPIOID USE DISORDER, DEMONSTRATES THAT PROLONGED EXPOSURE TO DRUGS OF ABUSE LEADS TO MARKED TRANSCRIPTIONAL AND EPIGENETIC DYSREGULATION IN LIMBIC SUBSTRUCTURES. IT IS WIDELY BELIEVED THAT THESE CHANGES IN GENE REGULATION IN RESPONSE TO DRUGS ARE A KEY DRIVING FACTOR IN THE PERPETUATION OF DRUG TAKING AND SEEKING BEHAVIORS. THUS, DEVELOPMENT OF INTERVENTIONS THAT COULD SHAPE TRANSCRIPTIONAL REGULATION IN RESPONSE TO DRUGS OF ABUSE WOULD BE OF HIGH VALUE. OVER THE PAST DECADE THERE HAS BEEN A SURGE IN RESEARCH DEMONSTRATING THAT THE RESIDENT BACTERIA OF THE GASTROINTESTINAL TRACT, COLLECTIVELY THE GUT MICROBIOME, CAN HAVE TREMENDOUS INFLUENCE ON NEUROBIOLOGICAL AND BEHAVIORAL PLASTICITY. PREVIOUS WORK FROM OUR GROUP AND OTHERS HAS DEMONSTRATED THAT ALTERATIONS IN THE GUT MICROBIOME CAN ALTER BEHAVIORAL RESPONSES TO OPIOIDS IN MULTIPLE PARADIGMS. ADDITIONALLY, WE HAVE PREVIOUSLY REPORTED THAT DEPLETION OF THE GUT MICROBIOME WITH ANTIBIOTICS MARKEDLY SHIFTS THE TRANSCRIPTOME OF THE NUCLEUS ACCUMBENS FOLLOWING PROLONGED MORPHINE EXPOSURE. IN THIS MANUSCRIPT WE PRESENT A COMPREHENSIVE ANALYSIS OF THE EFFECTS OF THE GUT MICROBIOME ON TRANSCRIPTIONAL REGULATION OF THE NUCLEUS ACCUMBENS FOLLOWING MORPHINE BY UTILIZING GERM-FREE, ANTIBIOTIC TREATED, AND CONTROL MICE. THIS ALLOWS FOR DETAILED UNDERSTANDING OF THE ROLE OF THE MICROBIOME IN REGULATING BASELINE TRANSCRIPTOMIC CONTROL, AS WELL AS RESPONSE TO MORPHINE. WE FIND THAT GERM-FREE STATUS LEADS TO A MARKED GENE DYSREGULATION IN A MANNER DISTINCT TO ADULT MICE TREATED WITH ANTIBIOTICS, AND THAT ALTERED GENE PATHWAYS ARE HIGHLY RELATED TO CELLULAR METABOLIC PROCESSES. THESE DATA PROVIDE ADDITIONAL INSIGHT INTO THE ROLE OF THE GUT MICROBIOME IN MODULATING BRAIN FUNCTION AND LAY A FOUNDATION FOR FURTHER STUDY IN THIS AREA. 2023 20 5926 34 TARGETING EPIGENETIC MECHANISMS FOR CHRONIC PAIN: A VALID APPROACH FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. CHRONIC PAIN IS A MULTIFACETED AND COMPLEX CONDITION. BROADLY CLASSIFIED INTO SOMATIC, VISCERAL, OR NEUROPATHIC PAIN, IT IS POORLY MANAGED DESPITE ITS PREVALENCE. CURRENT DRUGS USED FOR THE TREATMENT OF CHRONIC PAIN ARE LIMITED BY TOLERANCE WITH LONG-TERM USE, ABUSE POTENTIAL, AND MULTIPLE ADVERSE SIDE EFFECTS. THE PERSISTENT NATURE OF PAIN SUGGESTS THAT EPIGENETIC MACHINERY MAY BE A CRITICAL FACTOR DRIVING CHRONIC PAIN. IN THIS REVIEW, WE DISCUSS THE LATEST INSIGHTS INTO EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS, AND WE DESCRIBE THEIR INVOLVEMENT IN THE PATHOPHYSIOLOGY OF CHRONIC PAIN AND WHETHER EPIGENETIC MODIFICATIONS COULD BE APPLIED AS FUTURE THERAPEUTIC TARGETS FOR CHRONIC PAIN. WE PROVIDE EVIDENCE FROM EXPERIMENTAL MODELS AND TRANSLATIONAL RESEARCH IN HUMAN TISSUE THAT HAVE ENHANCED OUR UNDERSTANDING OF EPIGENETIC PROCESSES MEDIATING NOCICEPTION, AND WE THEN SPECULATE ON THE POTENTIAL FUTURE USE OF MORE SPECIFIC AND SELECTIVE AGENTS THAT TARGET EPIGENETIC MECHANISMS TO ATTENUATE PAIN. 2016