1 3952 98 LOCUS-SPECIFIC EPIGENETIC REMODELING CONTROLS ADDICTION- AND DEPRESSION-RELATED BEHAVIORS. CHRONIC EXPOSURE TO DRUGS OF ABUSE OR STRESS REGULATES TRANSCRIPTION FACTORS, CHROMATIN-MODIFYING ENZYMES AND HISTONE POST-TRANSLATIONAL MODIFICATIONS IN DISCRETE BRAIN REGIONS. GIVEN THE PROMISCUITY OF THE ENZYMES INVOLVED, IT HAS NOT YET BEEN POSSIBLE TO OBTAIN DIRECT CAUSAL EVIDENCE TO IMPLICATE THE REGULATION OF TRANSCRIPTION AND CONSEQUENT BEHAVIORAL PLASTICITY BY CHROMATIN REMODELING THAT OCCURS AT A SINGLE GENE. WE INVESTIGATED THE MECHANISM LINKING CHROMATIN DYNAMICS TO NEUROBIOLOGICAL PHENOMENA BY APPLYING ENGINEERED TRANSCRIPTION FACTORS TO SELECTIVELY MODIFY CHROMATIN AT A SPECIFIC MOUSE GENE IN VIVO. WE FOUND THAT HISTONE METHYLATION OR ACETYLATION AT THE FOSB LOCUS IN NUCLEUS ACCUMBENS, A BRAIN REWARD REGION, WAS SUFFICIENT TO CONTROL DRUG- AND STRESS-EVOKED TRANSCRIPTIONAL AND BEHAVIORAL RESPONSES VIA INTERACTIONS WITH THE ENDOGENOUS TRANSCRIPTIONAL MACHINERY. THIS APPROACH ALLOWED US TO RELATE THE EPIGENETIC LANDSCAPE AT A GIVEN GENE DIRECTLY TO REGULATION OF ITS EXPRESSION AND TO ITS SUBSEQUENT EFFECTS ON REWARD BEHAVIOR. 2014 2 883 39 CHRONIC COCAINE-REGULATED EPIGENOMIC CHANGES IN MOUSE NUCLEUS ACCUMBENS. BACKGROUND: INCREASING EVIDENCE SUPPORTS A ROLE FOR ALTERED GENE EXPRESSION IN MEDIATING THE LASTING EFFECTS OF COCAINE ON THE BRAIN, AND RECENT WORK HAS DEMONSTRATED THE INVOLVEMENT OF CHROMATIN MODIFICATIONS IN THESE ALTERATIONS. HOWEVER, ALL SUCH STUDIES TO DATE HAVE BEEN RESTRICTED BY THEIR RELIANCE ON MICROARRAY TECHNOLOGIES THAT HAVE INTRINSIC LIMITATIONS. RESULTS: WE USE NEXT GENERATION SEQUENCING METHODS, RNA-SEQ AND CHIP-SEQ FOR RNA POLYMERASE II AND SEVERAL HISTONE METHYLATION MARKS, TO OBTAIN A MORE COMPLETE VIEW OF COCAINE-INDUCED CHANGES IN GENE EXPRESSION AND ASSOCIATED ADAPTATIONS IN NUMEROUS MODES OF CHROMATIN REGULATION IN THE MOUSE NUCLEUS ACCUMBENS, A KEY BRAIN REWARD REGION. WE DEMONSTRATE AN UNEXPECTEDLY LARGE NUMBER OF PRE-MRNA SPLICING ALTERATIONS IN RESPONSE TO REPEATED COCAINE TREATMENT. IN ADDITION, WE IDENTIFY COMBINATIONS OF CHROMATIN CHANGES, OR SIGNATURES, THAT CORRELATE WITH COCAINE-DEPENDENT REGULATION OF GENE EXPRESSION, INCLUDING THOSE INVOLVING PRE-MRNA ALTERNATIVE SPLICING. THROUGH BIOINFORMATIC PREDICTION AND BIOLOGICAL VALIDATION, WE IDENTIFY ONE PARTICULAR SPLICING FACTOR, A2BP1(RBFOX1/FOX-1), WHICH IS ENRICHED AT GENES THAT DISPLAY CERTAIN CHROMATIN SIGNATURES AND CONTRIBUTES TO DRUG-INDUCED BEHAVIORAL ABNORMALITIES. TOGETHER, THIS DELINEATION OF THE COCAINE-INDUCED EPIGENOME IN THE NUCLEUS ACCUMBENS REVEALS SEVERAL NOVEL MODES OF REGULATION BY WHICH COCAINE ALTERS THE BRAIN. CONCLUSIONS: WE ESTABLISH COMBINATORIAL CHROMATIN AND TRANSCRIPTIONAL PROFILES IN MOUSE NUCLEUS ACCUMBENS AFTER REPEATED COCAINE TREATMENT. THESE RESULTS SERVE AS AN IMPORTANT RESOURCE FOR THE FIELD AND PROVIDE A TEMPLATE FOR THE ANALYSIS OF OTHER SYSTEMS TO REVEAL NEW TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS OF NEURONAL REGULATION. 2014 3 2280 42 EPIGENETIC REGULATION IN DRUG ADDICTION. THE INTERACTION BETWEEN ENVIRONMENTAL SIGNALS AND GENES HAS NOW TAKEN ON A CLEAR MOLECULAR FORM AS DEMONSTRATED BY STABLE CHANGES IN CHROMATIN STRUCTURE. THESE CHANGES OCCUR THROUGH ACTIVATION OR REPRESSION OF SPECIFIC GENE PROGRAMMES BY A COMBINATION OF CHROMATIN REMODELLING, ACTIVATION AND ENZYMATIC MODIFICATION OF DNA AND HISTONES AS WELL AS NUCLEOSOMAL SUBUNIT EXCHANGE. RECENT RESEARCH INVESTIGATING THE MOLECULAR MECHANISMS CONTROLLING DRUG-INDUCED TRANSCRIPTIONAL, BEHAVIOURAL AND SYNAPTIC ACTIVITY HAS SHOWN A DIRECT ROLE FOR CHROMATIN REMODELLING--TERMED AS EPIGENETIC REGULATION--OF NEURONAL GENE PROGRAMMES AND SUBSEQUENT ADDICTIVE BEHAVIOUR ARISING FROM IT. RECENT DATA SUGGEST THAT REPEATED EXPOSURE TO CERTAIN DRUGS PROMOTES CHANGES IN LEVELS OF HISTONE ACETYLATION, PHOSPHORYLATION AND METHYLATION, TOGETHER WITH ALTERATIONS IN DNA METHYLATION LEVELS IN THE NEURONS OF THE BRAIN REWARD CENTRE, LOCALISED IN THE NUCLEUS ACCUMBENS (NAC) REGION OF THE LIMBIC SYSTEM. THE COMBINATION OF ACETYLATING, PHOSPHORYLATING AND METHYLATING H3 AND H4 HISTONE TAILS ALTER CHROMATIN COMPACTION THEREBY PROMOTING ALTERED LEVELS OF CELLULAR GENE EXPRESSION. HISTONE MODIFICATIONS, WHICH WEAKEN HISTONE INTERACTION WITH DNA OR THAT PROMOTE RECRUITMENT OF TRANSCRIPTIONAL ACTIVATING COMPLEXES, CORRELATE WITH PERMISSIVE GENE EXPRESSION. HISTONE DEACETYLATION, (WHICH STRENGTHEN HISTONE: DNA CONTACTS), OR HISTONE METHYLATION, (WHICH RECRUITS REPRESSIVE COMPLEXES TO CHROMATIN), PROMOTE A STATE OF TRANSCRIPTIONAL REPRESSION. USING ANIMAL MODELS, ACUTE COCAINE TREATMENT INCREASES H4 ACETYLATION AT ACUTELY REGULATED GENE PROMOTERS, WHEREAS H3 ACETYLATION APPEARS TO PREDOMINATE AT CHRONICALLY INDUCED PROMOTERS. CHRONIC COCAINE AND ALCOHOL TREATMENT ACTIVATE AND REPRESS MANY GENES SUCH AS FOSB, CDK5, AND BDNF, WHERE THEIR DYSREGULATION, AT THE CHROMATIN LEVEL, CONTRIBUTE TO THE DEVELOPMENT AND MAINTENANCE OF ADDICTION. FOLLOWING DRUG EXPOSURE, IT IS STILL UNKNOWN, HOWVER, HOW LONG THESE CHANGES IN CHROMATIN STRUCTURE PERSIST IN AFFECTING NEURONAL FUNCTION, BUT SOME DO SO FOR LIFE. 2012 4 6517 30 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 5 6806 34 [EPIGENETICS AND DRUG ADDICTION: A FOCUS ON MECP2 AND ON HISTONE ACETYLATION]. CHRONIC DRUG EXPOSURE ALTERS GENE EXPRESSION IN THE BRAIN, WHICH IS BELIEVED TO UNDERLIE COMPULSIVE DRUG SEEKING AND DRUG TAKING BEHAVIOR. RECENT EVIDENCE SHOWS THAT DRUG-INDUCED LONG-TERM NEUROADAPTATIONS IN THE BRAIN ARE MEDIATED IN PART BY EPIGENETIC MECHANISMS. BY REMODELING CHROMATIN, THIS TYPE OF REGULATION CONTRIBUTES TO DRUG-INDUCED SYNAPTIC PLASTICITY THAT TRANSLATES INTO BEHAVIORAL MODIFICATIONS. HOW DRUG-INDUCED ALTERATIONS IN DNA METHYLATION REGULATE GENE EXPRESSION IS REVIEWED HERE, WITH A FOCUS ON MECP2, A PROTEIN BINDING METHYLATED DNA. THE IMPORTANCE OF HISTONE MODIFICATIONS, ESPECIALLY ACETYLATION IS ALSO DISCUSSED, WITH AN EMPHASIS ON THE EFFECTS OF INHIBITORS OF HISTONE DEACETYLASES ON DRUG-INDUCED BEHAVIORAL CHANGES. THE PRECISE IDENTIFICATION OF THE EPIGENETIC MECHANISMS THAT ARE UNDER THE CONTROL OF DRUGS OF ABUSE MAY HELP TO UNCOVER NOVEL TARGETS FOR THE TREATMENT OF DRUG SEEKING AND RELAPSE. 2015 6 2058 24 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 7 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 8 3375 37 HISTONE POSTTRANSLATIONAL MODIFICATIONS PREDICT SPECIFIC ALTERNATIVE EXON SUBTYPES IN MAMMALIAN BRAIN. A COMPELLING BODY OF LITERATURE, BASED ON NEXT GENERATION CHROMATIN IMMUNOPRECIPITATION AND RNA SEQUENCING OF REWARD BRAIN REGIONS INDICATES THAT THE REGULATION OF THE EPIGENETIC LANDSCAPE LIKELY UNDERLIES CHRONIC DRUG ABUSE AND ADDICTION. IT IS NOW CRITICAL TO DEVELOP HIGHLY INNOVATIVE COMPUTATIONAL STRATEGIES TO REVEAL THE RELEVANT REGULATORY TRANSCRIPTIONAL MECHANISMS THAT MAY UNDERLIE NEUROPSYCHIATRIC DISEASE. WE HAVE ANALYZED CHROMATIN REGULATION OF ALTERNATIVE SPLICING, WHICH IS IMPLICATED IN COCAINE EXPOSURE IN MICE. RECENT LITERATURE HAS DESCRIBED CHROMATIN-REGULATED ALTERNATIVE SPLICING, SUGGESTING A NOVEL FUNCTION FOR DRUG-INDUCED NEUROEPIGENETIC REMODELING. HOWEVER, THE EXTENT OF THE GENOME-WIDE ASSOCIATION BETWEEN PARTICULAR HISTONE MODIFICATIONS AND ALTERNATIVE SPLICING REMAINS UNEXPLORED. TO ADDRESS THIS, WE HAVE DEVELOPED NOVEL COMPUTATIONAL APPROACHES TO MODEL THE ASSOCIATION BETWEEN ALTERNATIVE SPLICING AND HISTONE POSTTRANSLATIONAL MODIFICATIONS IN THE NUCLEUS ACCUMBENS (NAC), A BRAIN REWARD REGION. USING CLASSICAL STATISTICAL METHODS AND MACHINE LEARNING TO COMBINE CHIP-SEQ AND RNA-SEQ DATA, WE FOUND THAT SPECIFIC HISTONE MODIFICATIONS ARE STRONGLY ASSOCIATED WITH VARIOUS ASPECTS OF DIFFERENTIAL SPLICING. H3K36ME3 AND H3K4ME1 HAVE THE STRONGEST ASSOCIATION WITH SPLICING INDICATING THEY PLAY A SIGNIFICANT ROLE IN ALTERNATIVE SPLICING IN BRAIN REWARD TISSUE. 2017 9 1532 24 DNA METHYLATION DYNAMICS AND COCAINE IN THE BRAIN: PROGRESS AND PROSPECTS. CYTOSINE MODIFICATIONS, INCLUDING DNA METHYLATION, ARE STABLE EPIGENETIC MARKS THAT MAY TRANSLATE ENVIRONMENTAL CHANGE INTO TRANSCRIPTIONAL REGULATION. RESEARCH HAS BEGUN TO INVESTIGATE DNA METHYLATION DYNAMICS IN RELATION TO COCAINE USE DISORDERS. SPECIFICALLY, DNA METHYLATION MACHINERY, INCLUDING METHYLTRANSFERASES AND BINDING PROTEINS, ARE DYSREGULATED IN BRAIN REWARD PATHWAYS AFTER CHRONIC COCAINE EXPOSURE. IN ADDITION, NUMEROUS METHYLOME-WIDE AND CANDIDATE PROMOTER STUDIES HAVE IDENTIFIED DIFFERENTIAL METHYLATION, AT THE NUCLEOTIDE LEVEL, IN RODENT MODELS OF COCAINE ABUSE AND DRUG SEEKING BEHAVIOR. THIS REVIEW HIGHLIGHTS THE CURRENT PROGRESS IN THE FIELD OF COCAINE-RELATED METHYLATION, AND OFFERS CONSIDERATIONS FOR FUTURE RESEARCH. 2017 10 2606 33 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 11 2013 28 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 12 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 13 5624 33 SELECTIVE BOOSTING OF TRANSCRIPTIONAL AND BEHAVIORAL RESPONSES TO DRUGS OF ABUSE BY HISTONE DEACETYLASE INHIBITION. HISTONE ACETYLATION AND OTHER MODIFICATIONS OF THE CHROMATIN ARE IMPORTANT REGULATORS OF GENE EXPRESSION AND, CONSEQUENTLY, MAY CONTRIBUTE TO DRUG-INDUCED BEHAVIORS AND NEUROPLASTICITY. EARLIER STUDIES HAVE SHOWN THAT A REDUCTION IN HISTONE DEACETYLASE (HDAC) ACTIVITY RESULTS IN THE ENHANCEMENT OF SOME PSYCHOSTIMULANT-INDUCED BEHAVIORS. IN THIS STUDY, WE EXTEND THOSE SEMINAL FINDINGS BY SHOWING THAT THE ADMINISTRATION OF THE HDAC INHIBITOR SODIUM BUTYRATE ENHANCES MORPHINE-INDUCED LOCOMOTOR SENSITIZATION AND CONDITIONED PLACE PREFERENCE. IN CONTRAST, THIS COMPOUND HAS NO EFFECTS ON THE DEVELOPMENT OF MORPHINE TOLERANCE AND DEPENDENCE. SIMILAR EFFECTS WERE OBSERVED FOR COCAINE AND ETHANOL-INDUCED BEHAVIORS. THESE BEHAVIORAL CHANGES WERE ACCOMPANIED BY A SELECTIVE BOOSTING OF A COMPONENT OF THE TRANSCRIPTIONAL PROGRAM ACTIVATED BY CHRONIC MORPHINE ADMINISTRATION THAT INCLUDED CIRCADIAN CLOCK GENES AND OTHER GENES RELEVANT TO ADDICTIVE BEHAVIOR. OUR RESULTS SUPPORT A SPECIFIC FUNCTION FOR HISTONE ACETYLATION AND THE EPIGENETIC MODULATION OF TRANSCRIPTION AT A REDUCED NUMBER OF BIOLOGICALLY RELEVANT LOCI ON NON-HOMEOSTATIC, LONG-LASTING, DRUG-INDUCED BEHAVIORAL PLASTICITY. 2009 14 2250 28 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 15 3376 26 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 16 1181 24 CONVERGENT ACTIONS OF STRESS AND STIMULANTS VIA EPIGENETIC REGULATION OF NEURAL CIRCUITRY. THE DORSAL STRIATUM INTEGRATES PRIOR AND CURRENT INFORMATION TO GUIDE APPROPRIATE DECISION-MAKING. CHRONIC STRESS AND STIMULANT EXPOSURE INTERFERES WITH DECISION-MAKING, AND CAN CONFER SIMILAR COGNITIVE AND BEHAVIORAL INFLEXIBILITIES. THIS REVIEW EXAMINES THE LITERATURE ON ACUTE AND CHRONIC REGULATION OF THE EPIGENOME BY STRESS AND STIMULANTS. RECENT EVIDENCE SUGGESTS THAT EXPOSURES TO STRESS AND STIMULANTS SHARE SIMILARITIES IN THE MANNERS IN WHICH THEY REGULATE THE DORSAL STRIATUM EPIGENOME THROUGH DNA METHYLATION, TRANSPOSABLE ELEMENT ACTIVITY, AND HISTONE POST-TRANSLATIONAL MODIFICATIONS. THESE FINDINGS SUGGEST THAT CHRONIC STRESS AND STIMULANT EXPOSURE LEADS TO THE ACCUMULATION OF EPIGENETIC MODIFICATIONS THAT IMPAIR IMMEDIATE AND FUTURE NEURON FUNCTION AND ACTIVITY. SUCH EPIGENETIC MECHANISMS REPRESENT POTENTIAL THERAPEUTIC TARGETS FOR AMELIORATING CONVERGENT SYMPTOMS OF STRESS AND ADDICTION. 2022 17 6400 32 THE ROLES OF CLASS I HISTONE DEACETYLASES (HDACS) IN MEMORY, LEARNING, AND EXECUTIVE COGNITIVE FUNCTIONS: A REVIEW. COORDINATED CHANGES IN GENE EXPRESSION ARE CRITICAL FOR SYNAPTIC PLASTICITY SUPPORTING LEARNING, MEMORY, AND OPTIMAL COGNITIVE TASK PERFORMANCE. THESE GENE EXPRESSION CHANGES ARE NOT ONLY MEDIATED BY SIGNALING PATHWAYS THAT ACTIVATE TRANSCRIPTION FACTORS, BUT ALSO BY CHROMATIN MODIFICATIONS THAT INFLUENCE THE ACCESSIBILITY OF THE TRANSCRIPTIONAL MACHINERY TO SPECIFIC GENOMIC REGIONS. DURING THE PAST DECADE, EVIDENCE ACCUMULATED THAT ALTERATIONS IN CHROMATIN-BASED EPIGENETIC REGULATION OF GENE EXPRESSION ARE LINKED TO COGNITIVE DYSFUNCTIONS IN THE AGEING OR NEURODEGENERATING BRAIN AS WELL AS TO COGNITIVE DYSFUNCTIONS RESULTING FROM CHRONIC STRESS EXPOSURE. THIS REVIEW SUMMARIZES THE RESULTS OF STUDIES THAT UNRAVELED A ROLE OF HISTONE MODIFYING ENZYMES AND HISTONE MODIFICATIONS IN NORMAL AND IMPAIRED LEARNING AND MEMORY, AND IN THE DISRUPTION OF EXECUTIVE COGNITIVE TASK PERFORMANCE. IT EMPHASIZES THE DIFFERENT ROLES OF SPECIFIC CLASS I HISTONE DEACETYLASES (HDACS) IN COGNITIVE PROCESSES GOVERNED BY THE HIPPOCAMPUS AND PREFRONTAL CORTEX AND DISCUSSES THE POTENTIAL THERAPEUTIC IMPLICATIONS OF TARGETING THEM TO HOLD THE PROGRESSION OF DISEASE-RELATED COGNITIVE DYSFUNCTIONS. 2017 18 2513 30 EPIGENETICS AND PSYCHOSTIMULANT ADDICTION. CHRONIC DRUG EXPOSURE ALTERS GENE EXPRESSION IN THE BRAIN AND PRODUCES LONG-TERM CHANGES IN NEURAL NETWORKS THAT UNDERLIE COMPULSIVE DRUG TAKING AND SEEKING. EXACTLY HOW DRUG-INDUCED CHANGES IN SYNAPTIC PLASTICITY AND SUBSEQUENT GENE EXPRESSION ARE TRANSLATED INTO PERSISTENT NEUROADAPTATIONS REMAINS UNCLEAR. EMERGING EVIDENCE SUGGESTS THAT COMPLEX DRUG-INDUCED NEUROADAPTATIONS IN THE BRAIN ARE MEDIATED BY HIGHLY SYNCHRONIZED AND DYNAMIC PATTERNS OF GENE REGULATION. RECENTLY, IT HAS BECOME CLEAR THAT EPIGENETIC MECHANISMS CONTRIBUTE TO DRUG-INDUCED STRUCTURAL, SYNAPTIC, AND BEHAVIORAL PLASTICITY BY REGULATING EXPRESSION OF GENE NETWORKS. HERE WE REVIEW HOW ALTERATIONS IN HISTONE MODIFICATIONS, DNA METHYLATION, AND MICRORNAS REGULATE GENE EXPRESSION AND CONTRIBUTE TO PSYCHOSTIMULANT ADDICTION WITH A FOCUS ON THE EPIGENETIC MECHANISMS THAT REGULATE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION FOLLOWING CHRONIC COCAINE EXPOSURE. IDENTIFYING EPIGENETIC SIGNATURES THAT DEFINE PSYCHOSTIMULANT ADDICTION MAY LEAD TO NOVEL, EFFICACIOUS TREATMENTS FOR DRUG CRAVING AND RELAPSE. 2013 19 4653 28 NEUROSCIENCE OF ALCOHOLISM: MOLECULAR AND CELLULAR MECHANISMS. ALCOHOL USE AND ABUSE APPEAR TO BE RELATED TO NEUROADAPTIVE CHANGES AT FUNCTIONAL, NEUROCHEMICAL, AND STRUCTURAL LEVELS. ACUTE AND CHRONIC ETHANOL EXPOSURE HAVE BEEN SHOWN TO MODULATE FUNCTION OF THE ACTIVITY-DEPENDENT GENE TRANSCRIPTION FACTOR, CAMP-RESPONSIVE ELEMENT BINDING (CREB) PROTEIN IN THE BRAIN, WHICH MAY BE ASSOCIATED WITH THE DEVELOPMENT OF ALCOHOLISM. STUDY OF THE DOWNSTREAM EFFECTORS OF CREB HAVE IDENTIFIED SEVERAL IMPORTANT CREB-RELATED GENES, SUCH AS NEUROPEPTIDE Y, BRAIN-DERIVED NEUROTROPHIC FACTOR, ACTIVITY-REGULATED CYTOSKELETON-ASSOCIATED PROTEIN, AND CORTICOTROPHIN-RELEASING FACTOR, THAT MAY PLAY A CRUCIAL ROLE IN THE BEHAVIORAL EFFECTS OF ETHANOL AND MOLECULAR CHANGES IN THE SPECIFIC NEUROCIRCUITRY THAT UNDERLIE BOTH ALCOHOL ADDICTION AND A GENETIC PREDISPOSITION TO ALCOHOLISM. BRAIN CHROMATIN REMODELING DUE TO HISTONE COVALENT MODIFICATIONS MAY ALSO BE INVOLVED IN MEDIATING THE BEHAVIORAL EFFECTS AND NEUROADAPTIVE CHANGES THAT OCCUR DURING ETHANOL EXPOSURE. THIS REVIEW OUTLINES PROGRESSIVE NEUROSCIENCE RESEARCH INTO MOLECULAR AND EPIGENETIC MECHANISMS OF ALCOHOLISM. 2010 20 110 22 A ROLE FOR ACTIVITY-DEPENDENT EPIGENETICS IN THE DEVELOPMENT AND TREATMENT OF MAJOR DEPRESSIVE DISORDER. CHRONIC STRESSORS, DURING DEVELOPMENTAL SENSITIVE PERIODS AND BEYOND, CONTRIBUTE TO THE RISK OF DEVELOPING PSYCHIATRIC CONDITIONS, INCLUDING MAJOR DEPRESSIVE DISORDER (MDD). EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS, AT KEY STRESS RESPONSE AND NEUROTROPHIN GENES, ARE INCREASINGLY IMPLICATED IN MEDIATING THIS RISK. ALTHOUGH THE EXACT MECHANISMS THROUGH WHICH STRESSFUL ENVIRONMENTAL STIMULI ALTER THE EPIGENOME ARE STILL UNCLEAR, RESEARCH FROM THE LEARNING AND MEMORY FIELDS INDICATES THAT EPIGENOMIC MARKS CAN BE ALTERED, AT LEAST IN PART, THROUGH CALCIUM-DEPENDENT SIGNALING CASCADES IN DIRECT RESPONSE TO NEURONAL ACTIVITY. IN THIS REVIEW, WE HIGHLIGHT KEY FINDINGS FROM THE STRESS, MDD, AND LEARNING AND MEMORY FIELDS TO PROPOSE A MODEL WHERE STRESS REGULATES DOWNSTREAM CELLULAR FUNCTIONING THROUGH ACTIVITY-DEPENDENT EPIGENETIC CHANGES. FURTHERMORE, WE SUGGEST THAT BOTH TYPICAL AND NOVEL ANTIDEPRESSANT TREATMENTS MAY EXERT POSITIVE INFLUENCE THROUGH SIMILAR, ACTIVITY-DEPENDENT PATHWAYS. 2018