1 2354 54 EPIGENETIC REGULATION OF PERSISTENT PAIN. PERSISTENT OR CHRONIC PAIN IS TIGHTLY ASSOCIATED WITH VARIOUS ENVIRONMENTAL CHANGES AND LINKED TO ABNORMAL GENE EXPRESSION WITHIN CELLS PROCESSING NOCICEPTIVE SIGNALING. EPIGENETIC REGULATION GOVERNS GENE EXPRESSION IN RESPONSE TO ENVIRONMENTAL CUES. RECENT ANIMAL MODEL AND CLINICAL STUDIES INDICATE THAT EPIGENETIC REGULATION PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT OR MAINTENANCE OF PERSISTENT PAIN AND POSSIBLY THE TRANSITION OF ACUTE PAIN TO CHRONIC PAIN, THUS SHEDDING LIGHT IN A DIRECTION FOR DEVELOPMENT OF NEW THERAPEUTICS FOR PERSISTENT PAIN. 2015 2 2259 20 EPIGENETIC PRIMING IN DRUG ADDICTION. DRUG ADDICTION IS A CHRONIC RELAPSING BRAIN DISORDER THAT IS CHARACTERIZED BY COMPULSIVE DRUG SEEKING AND CONTINUED USE DESPITE NEGATIVE OUTCOMES. CURRENT PHARMACOLOGICAL THERAPIES TARGET NEURONAL RECEPTORS OR TRANSPORTERS UPON WHICH DRUGS OF ABUSE ACT INITIALLY, YET THESE TREATMENTS REMAIN INEFFECTIVE FOR MOST INDIVIDUALS AND DO NOT PREVENT DISEASE RELAPSE AFTER ABSTINENCE. DRUGS OF ABUSE, IN ADDITION TO THEIR ACUTE EFFECTS, CAUSE PERSISTENT PLASTICITY AFTER REPEATED USE, INVOLVING DYSREGULATED GENE EXPRESSION IN THE BRAIN'S REWARD REGIONS, WHICH ARE THOUGHT TO MEDIATE THE PERSISTENT BEHAVIORAL ABNORMALITIES THAT CHARACTERIZE ADDICTION. EMERGING EVIDENCE IMPLICATES EPIGENETIC PRIMING AS A KEY MECHANISM THAT UNDERLIES THE LONG-LASTING ALTERATIONS IN NEURONAL GENE REGULATION, WHICH CAN REMAIN LATENT UNTIL TRIGGERED BY RE-EXPOSURE TO DRUG-ASSOCIATED STIMULI OR THE DRUG ITSELF. THUS, TO EFFECTIVELY TREAT DRUG ADDICTION, WE MUST IDENTIFY THE PRECISE EPIGENETIC MECHANISMS THAT ESTABLISH AND PRESERVE THE DRUG-INDUCED PATHOLOGY OF THE BRAIN REWARD CIRCUITRY. 2018 3 4049 20 MAKING MEMORIES THAT LAST A LIFETIME: HERITABLE FUNCTIONS OF SELF-RENEWING MEMORY CD8 T CELLS. CLONAL EXPANSION OF VIRUS-SPECIFIC NAIVE T CELLS DURING AN ACUTE VIRAL INFECTION RESULTS IN THE FORMATION OF MEMORY CD8 T CELLS THAT PROVIDE THE HOST WITH LONG-TERM PROTECTIVE IMMUNITY AGAINST THE PATHOGEN. MEMORY CD8 T CELLS DISPLAY ENHANCED EFFECTOR FUNCTIONS COMPARED WITH THEIR NAIVE PRECURSORS, ALLOWING THEM TO RESPOND MORE RAPIDLY AND EFFECTIVELY TO ANTIGEN RE-ENCOUNTER. THE ENHANCED FUNCTIONS OF MEMORY CD8 T CELLS ARE MEDIATED BY HERITABLE CHANGES IN GENE REGULATION. EXPRESSION OF SELECT TRANSCRIPTION FACTORS ALONG WITH LOCUS-SPECIFIC EPIGENETIC MODIFICATIONS ARE COUPLED TO AND ARE ESSENTIAL IN THE FORMATION OF MEMORY-SPECIFIC GENE EXPRESSION PATTERNS. HERE, WE WILL REVIEW THE CHANGES IN GENE EXPRESSION THAT ACCOMPANY DEVELOPMENT OF MEMORY CD8 T CELLS AND DISCUSS CHROMATIN MODIFICATIONS AS A POTENTIAL MEANS FOR HERITABLE PROPAGATION OF THESE CHANGES DURING HOMEOSTATIC CELL DIVISION OF SELF-RENEWING MEMORY CD8 T CELLS. ALSO, WE WILL DISCUSS THERAPIES THAT MANIPULATE HERITABLE GENE REGULATION AS A POTENTIAL MECHANISM TO RESTORE FUNCTION TO NON-FUNCTIONAL MEMORY CD8 T CELLS TO COMBAT CHRONIC VIRAL INFECTION. 2010 4 4386 17 MITOCHONDRIAL STRESS INDUCED BY CONTINUOUS STIMULATION UNDER HYPOXIA RAPIDLY DRIVES T CELL EXHAUSTION. CANCER AND CHRONIC INFECTIONS INDUCE T CELL EXHAUSTION, A HYPOFUNCTIONAL FATE CARRYING DISTINCT EPIGENETIC, TRANSCRIPTOMIC AND METABOLIC CHARACTERISTICS. HOWEVER, DRIVERS OF EXHAUSTION REMAIN POORLY UNDERSTOOD. AS INTRATUMORAL EXHAUSTED T CELLS EXPERIENCE SEVERE HYPOXIA, WE HYPOTHESIZED THAT METABOLIC STRESS ALTERS THEIR RESPONSES TO OTHER SIGNALS, SPECIFICALLY, PERSISTENT ANTIGENIC STIMULATION. IN VITRO, ALTHOUGH CD8(+) T CELLS EXPERIENCING CONTINUOUS STIMULATION OR HYPOXIA ALONE DIFFERENTIATED INTO FUNCTIONAL EFFECTORS, THE COMBINATION RAPIDLY DROVE T CELL DYSFUNCTION CONSISTENT WITH EXHAUSTION. CONTINUOUS STIMULATION PROMOTED BLIMP-1-MEDIATED REPRESSION OF PGC-1ALPHA-DEPENDENT MITOCHONDRIAL REPROGRAMMING, RENDERING CELLS POORLY RESPONSIVE TO HYPOXIA. LOSS OF MITOCHONDRIAL FUNCTION GENERATED INTOLERABLE LEVELS OF REACTIVE OXYGEN SPECIES (ROS), SUFFICIENT TO PROMOTE EXHAUSTED-LIKE STATES, IN PART THROUGH PHOSPHATASE INHIBITION AND THE CONSEQUENT ACTIVITY OF NUCLEAR FACTOR OF ACTIVATED T CELLS. REDUCING T CELL-INTRINSIC ROS AND LOWERING TUMOR HYPOXIA LIMITED T CELL EXHAUSTION, SYNERGIZING WITH IMMUNOTHERAPY. THUS, IMMUNOLOGIC AND METABOLIC SIGNALING ARE INTRINSICALLY LINKED: THROUGH MITIGATION OF METABOLIC STRESS, T CELL DIFFERENTIATION CAN BE ALTERED TO PROMOTE MORE FUNCTIONAL CELLULAR FATES. 2021 5 3731 19 INNATE AND ADAPTIVE IMMUNE REGULATION DURING CHRONIC VIRAL INFECTIONS. CHRONIC VIRAL INFECTIONS REPRESENT A UNIQUE CHALLENGE TO THE INFECTED HOST. PERSISTENTLY REPLICATING VIRUSES OUTCOMPETE OR SUBVERT THE INITIAL ANTIVIRAL RESPONSE, ALLOWING THE ESTABLISHMENT OF CHRONIC INFECTIONS THAT RESULT IN CONTINUOUS STIMULATION OF BOTH THE INNATE AND ADAPTIVE IMMUNE COMPARTMENTS. THIS CAUSES A PROFOUND REPROGRAMMING OF THE HOST IMMUNE SYSTEM, INCLUDING ATTENUATION AND PERSISTENT LOW LEVELS OF TYPE I INTERFERONS, PROGRESSIVE LOSS (OR EXHAUSTION) OF CD8(+) T CELL FUNCTIONS, AND SPECIALIZATION OF CD4(+) T CELLS TO PRODUCE INTERLEUKIN-21 AND PROMOTE ANTIBODY-MEDIATED IMMUNITY AND IMMUNE REGULATION. EPIGENETIC, TRANSCRIPTIONAL, POSTTRANSCRIPTIONAL, AND METABOLIC CHANGES UNDERLIE THIS ADAPTATION OR RECALIBRATION OF IMMUNE CELLS TO THE EMERGING NEW ENVIRONMENT IN ORDER TO STRIKE AN OFTEN IMPERFECT BALANCE BETWEEN THE HOST AND THE INFECTIOUS PATHOGEN. IN THIS REVIEW WE DISCUSS THE COMMON IMMUNOLOGICAL HALLMARKS OBSERVED ACROSS A RANGE OF DIFFERENT PERSISTENTLY REPLICATING VIRUSES AND HOST SPECIES, THE UNDERLYING MOLECULAR MECHANISMS, AND THE BIOLOGICAL AND CLINICAL IMPLICATIONS. 2015 6 1877 12 EMERGING ROLES OF EPIGENETIC MECHANISMS IN THE ENDURING EFFECTS OF EARLY-LIFE STRESS AND EXPERIENCE ON LEARNING AND MEMORY. EPIGENETIC MECHANISMS ARE INVOLVED IN PROGRAMMING GENE EXPRESSION THROUGHOUT DEVELOPMENT. IN ADDITION, THEY ARE KEY CONTRIBUTORS TO THE PROCESSES BY WHICH EARLY-LIFE EXPERIENCE FINE-TUNES THE EXPRESSION LEVELS OF KEY NEURONAL GENES, GOVERNING LEARNING AND MEMORY THROUGHOUT LIFE. HERE WE DESCRIBE THE LONG-LASTING, BI-DIRECTIONAL EFFECTS OF EARLY-LIFE EXPERIENCE ON LEARNING AND MEMORY. WE DISCUSS HOW ENRICHED POSTNATAL EXPERIENCE ENDURINGLY AUGMENTS SPATIAL LEARNING, AND HOW CHRONIC EARLY-LIFE STRESS RESULTS IN PERSISTENT AND PROGRESSIVE DEFICITS IN THE STRUCTURE AND FUNCTION OF HIPPOCAMPAL NEURONS. THE EXISTING AND EMERGING ROLES OF EPIGENETIC MECHANISMS IN THESE FUNDAMENTAL NEUROPLASTICITY PHENOMENA ARE ILLUSTRATED. 2011 7 2513 16 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 8 6706 19 VIRAL GENE PRODUCTS ACTIVELY PROMOTE LATENT INFECTION BY EPIGENETIC SILENCING MECHANISMS. MANY VIRUSES UNDERGO AN ACUTE INFECTION IN THE HOST ORGANISM AND THEN ARE CLEARED BY THE ENSUING HOST IMMUNE RESPONSE, BUT OTHER VIRUSES ESTABLISH A PERSISTENT INFECTION INVOLVING A LATENT INFECTION OR A CHRONIC INFECTION. LATENT INFECTION BY THE HERPESVIRUSES OR HUMAN IMMUNODEFICIENCY VIRUS INVOLVES EPIGENETIC SILENCING OF THE DNA GENOME OR PROVIRAL GENOME, RESPECTIVELY. LATENT INFECTION WAS PREVIOUSLY THOUGHT TO BE A DEFAULT PATHWAY RESULTING FROM INFECTION OF A NONPERMISSIVE CELL, BUT RECENT STUDIES HAVE SHOWN THAT VIRAL GENE PRODUCTS CAN PROMOTE EPIGENETIC SILENCING AND LATENT INFECTION. THIS REVIEW WILL SUMMARIZE THE VIRAL GENE PRODUCTS THAT HAVE BEEN SHOWN TO PROMOTE EPIGENETIC SILENCING OF THE GENOMES AND THEIR POTENTIAL FOR THERAPEUTICS TO TARGET THESE VIRAL GENE PRODUCTS AND DISRUPT OR LOCK IN LATENT INFECTION. 2017 9 2925 22 GENERATING LONG-LIVED CD8(+) T-CELL MEMORY: INSIGHTS FROM EPIGENETIC PROGRAMS. T-CELL-BASED IMMUNOLOGICAL MEMORY HAS THE POTENTIAL TO PROVIDE THE HOST WITH LIFE-LONG PROTECTION AGAINST PATHOGEN REEXPOSURE AND THUS OFFERS TREMENDOUS PROMISE FOR THE DESIGN OF VACCINES TARGETING CHRONIC INFECTIONS OR CANCER. IN ORDER TO EXPLOIT THIS POTENTIAL IN THE DESIGN OF NEW VACCINES, IT IS NECESSARY TO UNDERSTAND HOW AND WHEN MEMORY T CELLS ACQUIRE THEIR POISED EFFECTOR POTENTIAL, AND MOREOVER, HOW THEY MAINTAIN THESE PROPERTIES DURING HOMEOSTATIC PROLIFERATION. TO GAIN INSIGHT INTO THE PERSISTENT NATURE OF MEMORY T-CELL FUNCTIONS, INVESTIGATORS HAVE TURNED THEIR ATTENTION TO EPIGENETIC MECHANISMS. RECENT EFFORTS HAVE REVEALED THAT MANY OF THE PROPERTIES ACQUIRED AMONG MEMORY T CELLS ARE COUPLED TO STABLE CHANGES IN DNA METHYLATION AND HISTONE MODIFICATIONS. FURTHERMORE, IT HAS RECENTLY BEEN REPORTED THAT THE DELINEATING FEATURES AMONG MEMORY T CELLS SUBSETS ARE ALSO LINKED TO DISTINCT EPIGENETIC EVENTS, SUCH AS PERMISSIVE AND REPRESSIVE HISTONE MODIFICATIONS AND DNA METHYLATION PROGRAMS, PROVIDING EXCITING NEW HYPOTHESES REGARDING THEIR CELLULAR ANCESTRY. HERE, WE REVIEW RECENT STUDIES FOCUSED ON EPIGENETIC PROGRAMS ACQUIRED DURING EFFECTOR AND MEMORY T-CELL DIFFERENTIATION AND DISCUSS HOW THESE DATA MAY SHED NEW LIGHT ON THE DEVELOPMENTAL PATH FOR GENERATING LONG-LIVED CD8(+) T-CELL MEMORY. 2016 10 2292 18 EPIGENETIC REGULATION IN SUBSTANCE USE DISORDERS. SUBSTANCE USE DISORDER IS A CHRONIC CONDITION OF COMPULSIVE DRUG SEEKING AND USE THAT IS MEDIATED BY STABLE CHANGES IN CENTRAL REWARD PATHWAYS. REPEATED USE OF ABUSED DRUGS CAUSES PERSISTENT ALTERATIONS IN GENE EXPRESSION RESPONSIBLE FOR THE LONG-TERM BEHAVIORAL AND STRUCTURAL CHANGES. RECENTLY, IT HAS BEEN SUGGESTED THAT EPIGENETIC MECHANISMS ARE RESPONSIBLE IN PART FOR THESE DRUG-INDUCED CHANGES IN GENE EXPRESSION. ONE OF THE ALLURING ASPECTS OF EPIGENETIC REGULATION OF GENE EXPRESSION IS THAT EPIGENETIC MECHANISMS MAY PROVIDE TRANSIENT AND POTENTIALLY STABLE CONDITIONS THAT IN TURN MAY ULTIMATELY PARTICIPATE IN THE MOLECULAR MECHANISMS REQUIRED FOR NEURONAL CHANGES SUBSERVING LONG-LASTING CHANGES IN BEHAVIOR. THIS REVIEW DESCRIBES EPIGENETIC MECHANISMS OF GENE REGULATION AND THEN DISCUSSES THE EMERGING ROLE OF EPIGENETICS IN DRUG-INDUCED PLASTICITY AND BEHAVIOR. UNDERSTANDING THESE MECHANISMS THAT ESTABLISH AND MAINTAIN DRUG-DEPENDENT PLASTICITY CHANGES MAY LEAD TO DEEPER UNDERSTANDING OF SUBSTANCE USE DISORDERS AS WELL AS NOVEL APPROACHES TO TREATMENT. 2010 11 6365 17 THE ROLE OF METABOLIC DYSFUNCTION IN T-CELL EXHAUSTION DURING CHRONIC VIRAL INFECTION. T CELLS ARE IMPORTANT COMPONENTS OF ADAPTIVE IMMUNITY THAT PROTECT THE HOST AGAINST INVADING PATHOGENS DURING INFECTION. UPON RECOGNIZING THE ACTIVATION SIGNALS, NAIVE AND/OR MEMORY T CELLS WILL INITIATE CLONAL EXPANSION, TRIGGER DIFFERENTIATION INTO EFFECTOR POPULATIONS AND TRAFFIC TO THE INFLAMED SITES TO ELIMINATE PATHOGENS. HOWEVER, IN CHRONIC VIRAL INFECTIONS, SUCH AS THOSE CAUSED BY HUMAN IMMUNODEFICIENCY VIRUS (HIV), HEPATITIS B AND C (HBV AND HCV), T CELLS EXHIBIT IMPAIRED FUNCTION AND BECOME DIFFICULT TO CLEAR PATHOGENS IN A STATE KNOWN AS T-CELL EXHAUSTION. THE ACTIVATION AND FUNCTION PERSISTENCE OF T CELLS DEMAND FOR DYNAMIC CHANGES IN CELLULAR METABOLISM TO MEET THEIR BIOENERGETIC AND BIOSYNTHETIC DEMANDS, ESPECIALLY THE AUGMENTATION OF AEROBIC GLYCOLYSIS, WHICH NOT ONLY PROVIDE EFFICIENT ENERGY GENERATION, BUT ALSO FUEL MULTIPLE BIOCHEMICAL INTERMEDIATES THAT ARE ESSENTIAL FOR NUCLEOTIDE, AMINO ACID, FATTY ACID SYNTHESIS AND MITOCHONDRIA FUNCTION. CHANGES IN CELLULAR METABOLISM ALSO AFFECT THE FUNCTION OF EFFECTORS T CELLS THROUGH MODIFYING EPIGENETIC SIGNATURES. IT IS WIDELY ACCEPTED THAT THE DYSFUNCTION OF T CELL METABOLISM CONTRIBUTES GREATLY TO T-CELL EXHAUSTION. HERE, WE REVIEWED RECENT FINDINGS ON T CELLS METABOLISM UNDER CHRONIC VIRAL INFECTION, SEEKING TO REVEAL THE ROLE OF METABOLIC DYSFUNCTION PLAYED IN T-CELL EXHAUSTION. 2022 12 4650 16 NEUROPLASTICITY IN ADDICTION: CELLULAR AND TRANSCRIPTIONAL PERSPECTIVES. DRUG ADDICTION IS A CHRONIC, RELAPSING BRAIN DISORDER WHICH CONSISTS OF COMPULSIVE PATTERNS OF DRUG-SEEKING AND TAKING THAT OCCURS AT THE EXPENSE OF OTHER ACTIVITIES. THE TRANSITION FROM CASUAL TO COMPULSIVE DRUG USE AND THE ENDURING PROPENSITY TO RELAPSE IS THOUGHT TO BE UNDERPINNED BY LONG-LASTING NEUROADAPTATIONS IN SPECIFIC BRAIN CIRCUITRY, ANALOGOUS TO THOSE THAT UNDERLIE LONG-TERM MEMORY FORMATION. RESEARCH SPANNING THE LAST TWO DECADES HAS MADE GREAT PROGRESS IN IDENTIFYING CELLULAR AND MOLECULAR MECHANISMS THAT CONTRIBUTE TO DRUG-INDUCED CHANGES IN PLASTICITY AND BEHAVIOR. ALTERATIONS IN SYNAPTIC TRANSMISSION WITHIN THE MESOCORTICOLIMBIC AND CORTICOSTRIATAL PATHWAYS, AND CHANGES IN THE TRANSCRIPTIONAL POTENTIAL OF CELLS BY EPIGENETIC MECHANISMS ARE TWO IMPORTANT MEANS BY WHICH DRUGS OF ABUSE CAN INDUCE LASTING CHANGES IN BEHAVIOR. IN THIS REVIEW WE PROVIDE A SUMMARY OF MORE RECENT RESEARCH THAT HAS FURTHERED OUR UNDERSTANDING OF DRUG-INDUCED NEUROPLASTIC CHANGES BOTH AT THE LEVEL OF THE SYNAPSE, AND ON A TRANSCRIPTIONAL LEVEL, AND HOW THESE CHANGES MAY RELATE TO THE HUMAN DISEASE OF ADDICTION. 2012 13 5704 21 SINGLE-CELL RNA-SEQ REVEALS TOX AS A KEY REGULATOR OF CD8(+) T CELL PERSISTENCE IN CHRONIC INFECTION. PROGENITOR-LIKE CD8(+) T CELLS MEDIATE LONG-TERM IMMUNITY TO CHRONIC INFECTION AND CANCER AND RESPOND POTENTLY TO IMMUNE CHECKPOINT BLOCKADE. THESE CELLS SHARE TRANSCRIPTIONAL REGULATORS WITH MEMORY PRECURSOR CELLS, INCLUDING T CELL-SPECIFIC TRANSCRIPTION FACTOR 1 (TCF1), BUT IT IS UNCLEAR WHETHER THEY ADOPT DISTINCT PROGRAMS TO ADAPT TO THE IMMUNOSUPPRESSIVE ENVIRONMENT. BY COMPARING THE SINGLE-CELL TRANSCRIPTOMES AND EPIGENETIC PROFILES OF CD8(+) T CELLS RESPONDING TO ACUTE AND CHRONIC VIRAL INFECTIONS, WE FOUND THAT PROGENITOR-LIKE CD8(+) T CELLS BECAME DISTINCT FROM MEMORY PRECURSOR CELLS BEFORE THE PEAK OF THE T CELL RESPONSE. WE DISCOVERED A COEXPRESSION GENE MODULE CONTAINING TOX THAT EXHIBITED HIGHER TRANSCRIPTIONAL ACTIVITY ASSOCIATED WITH MORE ABUNDANT ACTIVE HISTONE MARKS IN PROGENITOR-LIKE CELLS THAN MEMORY PRECURSOR CELLS. MOREOVER, THYMOCYTE SELECTION-ASSOCIATED HIGH MOBILITY GROUP BOX PROTEIN TOX (TOX) PROMOTED THE PERSISTENCE OF ANTIVIRAL CD8(+) T CELLS AND WAS REQUIRED FOR THE PROGRAMMING OF PROGENITOR-LIKE CD8(+) T CELLS. THUS, LONG-TERM CD8(+) T CELL IMMUNITY TO CHRONIC VIRAL INFECTION REQUIRES UNIQUE TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS ASSOCIATED WITH THE TRANSCRIPTION FACTOR TOX. 2019 14 4036 19 MACROPHAGE EPIGENETIC MEMORIES OF EARLY LIFE INJURY DRIVE NEONATAL NOCICEPTIVE PRIMING. THE DEVELOPING PERIPHERAL NERVOUS AND IMMUNE SYSTEMS ARE FUNCTIONALLY DISTINCT FROM ADULTS. THESE SYSTEMS ARE VULNERABLE TO EFFECTS OF EARLY LIFE INJURY WHICH CAN INFLUENCE OUTCOMES RELATED TO NOCICEPTION FOLLOWING SUBSEQUENT INJURY LATER IN LIFE (I.E. "NEONATAL NOCICEPTIVE PRIMING"). THE UNDERPINNINGS OF THIS PHENOMENON ARE LARGELY UNKNOWN, ALTHOUGH MACROPHAGES CAN BE EPIGENETICALLY TRAINED BY INJURY. WE FOUND THAT MACROPHAGES ARE BOTH NECESSARY AND PARTIALLY SUFFICIENT TO DRIVE NEONATAL NOCICEPTIVE PRIMING POSSIBLY DUE TO A LONG-LASTING EPIGENETIC REMODELING OF PERIPHERAL MACROPHAGES. THE P75 NEUROTROPHIC FACTOR RECEPTOR (NTR) WAS OBSERVED TO BE AN IMPORTANT EFFECTOR IN REGULATING NEONATAL NOCICEPTIVE PRIMING. P75NTR MODULATES THE INFLAMMATORY PROFILE AND RESPONSES OF RODENT AND HUMAN MACROPHAGES. THIS "PAIN MEMORY" WAS ABLE TO BE TRANSFERRED TO A NAIVE HOST TO ALTER SEX-SPECIFIC PAIN-RELATED BEHAVIORS. THIS STUDY REVEALS A NOVEL MECHANISM BY WHICH ACUTE POST-SURGICAL PAIN MAY TRANSITION TO CHRONIC PAIN IN CHILDREN. 2023 15 584 28 BEHAVIORAL NEUROADAPTATION TO ALCOHOL: FROM GLUCOCORTICOIDS TO HISTONE ACETYLATION. A PRIME MECHANISM THAT CONTRIBUTES TO THE DEVELOPMENT AND MAINTENANCE OF ALCOHOLISM IS THE DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS ACTIVITY AND THE RELEASE OF GLUCOCORTICOIDS (CORTISOL IN HUMANS AND PRIMATES, CORTICOSTERONE IN RODENTS) FROM THE ADRENAL GLANDS. IN THE BRAIN, SUSTAINED, LOCAL ELEVATION OF GLUCOCORTICOID CONCENTRATION EVEN LONG AFTER CESSATION OF CHRONIC ALCOHOL CONSUMPTION COMPROMISES FUNCTIONAL INTEGRITY OF A CIRCUIT, INCLUDING THE PREFRONTAL CORTEX (PFC), THE HIPPOCAMPUS (HPC), AND THE AMYGDALA (AMG). THESE STRUCTURES ARE IMPLICATED IN LEARNING AND MEMORY PROCESSES AS WELL AS IN ORCHESTRATING NEUROADAPTIVE RESPONSES TO STRESS AND ANXIETY RESPONSES. THUS, POTENTIATION OF ANXIETY-RELATED NEUROADAPTATION BY ALCOHOL IS CHARACTERIZED BY AN ABNORMALLY AMG HYPERACTIVITY COUPLED WITH A HYPOFUNCTION OF THE PFC AND THE HPC. THIS REVIEW DESCRIBES RESEARCH ON MOLECULAR AND EPIGENETIC MECHANISMS BY WHICH ALCOHOL CAUSES DISTINCT REGION-SPECIFIC ADAPTIVE CHANGES IN GENE EXPRESSION PATTERNS AND ULTIMATELY LEADS TO A VARIETY OF COGNITIVE AND BEHAVIORAL IMPAIRMENTS ON PREFRONTAL- AND HIPPOCAMPAL-BASED TASKS. ALCOHOL-INDUCED NEUROADAPTATIONS INVOLVE THE DYSREGULATION OF NUMEROUS SIGNALING CASCADES, LEADING TO LONG-TERM CHANGES IN TRANSCRIPTIONAL PROFILES OF GENES, THROUGH THE ACTIONS OF TRANSCRIPTION FACTORS SUCH AS [CAMP RESPONSE ELEMENT-BINDING PROTEIN (CREB)] AND CHROMATIN REMODELING DUE TO POSTTRANSLATIONAL MODIFICATIONS OF HISTONE PROTEINS. WE DESCRIBE THE ROLE OF PREFRONTAL-HPC-AMG CIRCUIT IN MEDIATING THE EFFECTS OF ACUTE AND CHRONIC ALCOHOL ON LEARNING AND MEMORY, AND REGION-SPECIFIC MOLECULAR AND EPIGENETIC MECHANISMS INVOLVED IN THIS PROCESS. THIS REVIEW FIRST DISCUSSES THE IMPORTANCE OF BRAIN REGION-SPECIFIC DYSREGULATION OF GLUCOCORTICOID CONCENTRATION IN THE DEVELOPMENT OF ALCOHOL DEPENDENCE AND DESCRIBES HOW PERSISTENTLY INCREASED GLUCOCORTICOID LEVELS IN PFC MAY BE INVOLVED IN MEDIATING WORKING MEMORY IMPAIRMENTS AND NEUROADAPTIVE CHANGES DURING WITHDRAWAL FROM CHRONIC ALCOHOL INTAKE. IT THEN HIGHLIGHTS THE ROLE OF CAMP-PKA-CREB SIGNALING CASCADE AND HISTONE ACETYLATION WITHIN THE PFC AND LIMBIC STRUCTURES IN ALCOHOL-INDUCED ANXIETY AND BEHAVIORAL IMPAIRMENTS, AND HOW AN UNDERSTANDING OF FUNCTIONAL ALTERATIONS OF THESE PATHWAYS MIGHT LEAD TO BETTER TREATMENTS FOR NEUROPSYCHIATRIC DISORDERS. 2016 16 1181 14 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 2145 18 EPIGENETIC MAINTENANCE OF ACQUIRED GENE EXPRESSION PROGRAMS DURING MEMORY CD8 T CELL HOMEOSTASIS. MEMORY CD8 T CELLS HAVE A UNIQUE ABILITY TO PROVIDE LIFELONG IMMUNITY AGAINST PATHOGENS CONTAINING THEIR COGNATE EPITOPE. BECAUSE OF THEIR ABILITY TO PROVIDE LIFELONG PROTECTION, THE GENERATION OF MEMORY T CELLS IS NOW A MAJOR FOCUS FOR CURRENT VACCINATION OR ADOPTIVE CELL THERAPY APPROACHES TO TREAT CHRONIC VIRAL INFECTIONS AND CANCER. IT IS NOW CLEAR THAT MAINTENANCE OF MEMORY CD8 T CELLS OCCURS THROUGH A PROCESS OF ANTIGEN-INDEPENDENT HOMEOSTATIC PROLIFERATION, WHICH IS REGULATED IN PART BY THE GAMMA CHAIN CYTOKINES IL-7 AND IL-15. HERE, WE WILL DESCRIBE THE ROLE OF THESE CYTOKINES IN THE SURVIVAL AND SELF-RENEWAL OF MEMORY CD8 T CELLS. FURTHER, WE WILL DESCRIBE THE ROLE OF EPIGENETICS IN THE MAINTENANCE OF ACQUIRED FUNCTIONS AMONG MEMORY CD8 T CELLS DURING HOMEOSTATIC PROLIFERATION. 2018 18 6677 21 USING EPIGENETICS TO DEFINE VACCINE-INDUCED MEMORY T CELLS. MEMORY T CELLS GENERATED FROM ACUTE INFECTION OR VACCINATION HAVE THE POTENTIAL TO PROVIDE THE HOST WITH LIFE-LONG IMMUNITY AGAINST RE-INFECTION. PROTECTION BY MEMORY T CELLS IS ACHIEVED THROUGH THEIR ACQUIRED ABILITY TO PERSIST AT ANATOMICAL SITES OF THE PRIMARY INFECTION AS WELL AS MAINTAINING A HEIGHTENED ABILITY TO RECALL EFFECTOR FUNCTIONS. THE MAINTENANCE OF CD8 AND CD4 T CELL FUNCTION IN A STATE OF READINESS IS KEY TO LIFE-LONG IMMUNITY AND MANIFEST THROUGH CHANGES IN TRANSCRIPTIONAL REGULATION. YET, THE ABILITY TO IDENTIFY POISED TRANSCRIPTIONAL PROGRAMS AT THE MAINTENANCE STAGE OF THE RESPONSE IS LACKING FROM MOST TRANSCRIPTIONAL PROFILING STUDIES OF MEMORY T CELLS. EPIGENETIC PROFILING ALLOWS FOR THE ASSESSMENT OF TRANSCRIPTIONALLY POISED (PROMOTERS THAT ARE READILY ACCESSIBLE FOR TRANSCRIPTION) STATES OF ANTIGEN-SPECIFIC T CELLS WITHOUT MANIPULATION OF THE ACTIVATION STATE OF THE CELL. HERE WE REVIEW RECENT STUDIES THAT HAVE EXAMINED EPIGENETIC PROGRAMS OF EFFECTOR AND MEMORY T CELL SUBSETS. THESE REPORTS DEMONSTRATE THAT ACQUISITION OF EPIGENETIC PROGRAMS DURING MEMORY T CELL DIFFERENTIATION TO ACUTE AND CHRONIC INFECTIONS IS COUPLED TO, AND POTENTIALLY REGULATE, THE CELL'S RECALL RESPONSE. WE DISCUSS THE USEFULNESS OF EPIGENETIC PROFILING IN CHARACTERIZING T CELL DIFFERENTIATION STATE AND FUNCTION FOR PRECLINICAL EVALUATION OF VACCINES AND THE CURRENT METHODOLOGIES FOR SINGLE LOCUS VERSUS GENOME-WIDE EPIGENETIC PROFILING. 2013 19 2280 24 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 20 2410 16 EPIGENETIC SCARS OF CD8(+) T CELL EXHAUSTION PERSIST AFTER CURE OF CHRONIC INFECTION IN HUMANS. T CELL EXHAUSTION IS AN INDUCED STATE OF DYSFUNCTION THAT ARISES IN RESPONSE TO CHRONIC INFECTION AND CANCER. EXHAUSTED CD8(+) T CELLS ACQUIRE A DISTINCT EPIGENETIC STATE, BUT IT IS NOT KNOWN WHETHER THAT CHROMATIN LANDSCAPE IS FIXED OR PLASTIC FOLLOWING THE RESOLUTION OF A CHRONIC INFECTION. HERE WE SHOW THAT THE EPIGENETIC STATE OF EXHAUSTION IS LARGELY IRREVERSIBLE, EVEN AFTER CURATIVE THERAPY. ANALYSIS OF CHROMATIN ACCESSIBILITY IN HCV- AND HIV-SPECIFIC RESPONSES IDENTIFIES A CORE EPIGENETIC PROGRAM OF EXHAUSTION IN CD8(+) T CELLS, WHICH UNDERGOES ONLY LIMITED REMODELING BEFORE AND AFTER RESOLUTION OF INFECTION. MOREOVER, CANONICAL FEATURES OF EXHAUSTION, INCLUDING SUPER-ENHANCERS NEAR THE GENES TOX AND HIF1A, REMAIN 'EPIGENETICALLY SCARRED.' T CELL EXHAUSTION IS THEREFORE A CONSERVED EPIGENETIC STATE THAT BECOMES FIXED AND PERSISTS INDEPENDENT OF CHRONIC ANTIGEN STIMULATION AND INFLAMMATION. THERAPEUTIC EFFORTS TO REVERSE T CELL EXHAUSTION MAY REQUIRE NEW APPROACHES THAT INCREASE THE EPIGENETIC PLASTICITY OF EXHAUSTED T CELLS. 2021