1 4049 94 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 2 6677 41 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 3 2925 39 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 4 2671 32 ETHANOL CONSUMPTION INDUCES NONSPECIFIC INFLAMMATION AND FUNCTIONAL DEFECTS IN ALVEOLAR MACROPHAGES. CHRONIC ALCOHOL DRINKING IS ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO VIRAL AND BACTERIAL RESPIRATORY PATHOGENS. IN THIS STUDY, WE USE A RHESUS MACAQUE MODEL OF VOLUNTARY ETHANOL SELF-ADMINISTRATION TO STUDY THE EFFECTS OF LONG-TERM ALCOHOL DRINKING ON THE IMMUNOLOGICAL LANDSCAPE OF THE LUNG. WE REPORT A HEIGHTENED INFLAMMATORY STATE IN ALVEOLAR MACROPHAGES (AMS) OBTAINED FROM ETHANOL (ETOH)-DRINKING ANIMALS THAT IS ACCOMPANIED BY INCREASED CHROMATIN ACCESSIBILITY IN INTERGENIC REGIONS THAT REGULATE INFLAMMATORY GENES AND CONTAIN BINDING MOTIFS FOR TRANSCRIPTION FACTORS AP-1, IRF8, AND NFKB P-65. IN LINE WITH THESE TRANSCRIPTIONAL AND EPIGENETIC CHANGES AT THE BASAL STATE, AMS FROM ETOH-DRINKING ANIMALS GENERATE ELEVATED INFLAMMATORY MEDIATOR RESPONSES TO LIPOPOLYSACCHARIDES AND RESPIRATORY SYNCYTIAL VIRUS. HOWEVER, THE TRANSCRIPTIONAL ANALYSIS REVEALED AN INEFFICIENT INDUCTION OF INTERFERON-STIMULATED GENES WITH ETOH IN RESPONSE TO THE RESPIRATORY SYNCYTIAL VIRUS, SUGGESTING DISRUPTION OF ANTIMICROBIAL DEFENSES. CORRESPONDINGLY, AMS FROM ETOH-DRINKING ANIMALS EXHIBITED TRANSCRIPTIONAL SHIFTS INDICATIVE OF INCREASED OXIDATIVE STRESS AND OXIDATIVE PHOSPHORYLATION, WHICH WAS COUPLED WITH HIGHER CYTOSOLIC REACTIVE OXYGEN SPECIES AND MITOCHONDRIAL POTENTIAL. THIS HEIGHTENED OXIDATIVE STRESS STATE WAS ACCOMPANIED BY DECREASED ABILITY TO PHAGOCYTOSE BACTERIA. BULK RNA AND ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN SEQUENCING DATA FURTHER REVEALED REDUCED EXPRESSION AND CHROMATIN ACCESSIBILITY OF LOCI ASSOCIATED WITH TISSUE REPAIR AND MAINTENANCE WITH CHRONIC ETOH DRINKING. SIMILARLY, ANALYSIS OF SINGLE-CELL RNA SEQUENCING DATA REVEALED SHIFTS IN CELL STATES FROM TISSUE MAINTENANCE TO INFLAMMATORY RESPONSES WITH ETOH. COLLECTIVELY, THESE DATA PROVIDE NOVEL INSIGHT INTO MECHANISMS BY WHICH CHRONIC ETOH DRINKING INCREASES SUSCEPTIBILITY TO INFECTION IN PATIENTS WITH ALCOHOL USE DISORDERS. 2022 5 3738 29 INORGANIC ARSENIC-INDUCED CELLULAR TRANSFORMATION IS COUPLED WITH GENOME WIDE CHANGES IN CHROMATIN STRUCTURE, TRANSCRIPTOME AND SPLICING PATTERNS. BACKGROUND: ARSENIC (AS) EXPOSURE IS A SIGNIFICANT WORLDWIDE ENVIRONMENTAL HEALTH CONCERN. LOW DOSE, CHRONIC ARSENIC EXPOSURE HAS BEEN ASSOCIATED WITH A HIGHER THAN NORMAL RISK OF SKIN, LUNG, AND BLADDER CANCER, AS WELL AS CARDIOVASCULAR DISEASE AND DIABETES. WHILE ARSENIC-INDUCED BIOLOGICAL CHANGES PLAY A ROLE IN DISEASE PATHOLOGY, LITTLE IS KNOWN ABOUT THE DYNAMIC CELLULAR CHANGES RESULTING FROM ARSENIC EXPOSURE AND WITHDRAWAL. RESULTS: IN THESE STUDIES, WE SOUGHT TO UNDERSTAND THE MOLECULAR MECHANISMS BEHIND THE BIOLOGICAL CHANGES INDUCED BY ARSENIC EXPOSURE. A COMPREHENSIVE GLOBAL APPROACH WAS EMPLOYED TO DETERMINE GENOME-WIDE CHANGES TO CHROMATIN STRUCTURE, TRANSCRIPTOME PATTERNS AND SPLICING PATTERNS IN RESPONSE TO CHRONIC LOW DOSE ARSENIC AND ITS SUBSEQUENT WITHDRAWAL. OUR RESULTS SHOW THAT CELLS EXPOSED TO CHRONIC LOW DOSES OF SODIUM ARSENITE HAVE DISTINCT TEMPORAL AND COORDINATED CHROMATIN, GENE EXPRESSION, AND MIRNA CHANGES CONSISTENT WITH DIFFERENTIATION AND ACTIVATION OF MULTIPLE BIOCHEMICAL PATHWAYS. MOST OF THESE TEMPORAL PATTERNS IN GENE EXPRESSION ARE REVERSED WHEN ARSENIC IS WITHDRAWN. HOWEVER, SOME GENE EXPRESSION PATTERNS REMAINED ALTERED, PLAUSIBLY AS A RESULT OF AN ADAPTIVE RESPONSE BY CELLS. ADDITIONALLY, THE CORRELATION OF CHANGES TO GENE EXPRESSION AND CHROMATIN STRUCTURE SOLIDIFY THE ROLE OF CHROMATIN STRUCTURE IN GENE REGULATORY CHANGES DUE TO ARSENITE EXPOSURE. LASTLY, WE SHOW THAT ARSENITE EXPOSURE INFLUENCES GENE REGULATION BOTH AT THE INITIATION OF TRANSCRIPTION AS WELL AS AT THE LEVEL OF SPLICING. CONCLUSIONS: OUR RESULTS SHOW THAT ADAPTATION OF CELLS TO IAS-MEDIATED EMT IS COUPLED TO CHANGES IN CHROMATIN STRUCTURE EFFECTING DIFFERENTIAL TRANSCRIPTIONAL AND SPLICING PATTERNS OF GENES. THESE STUDIES PROVIDE NEW INSIGHTS INTO THE MECHANISM OF IAS-MEDIATED PATHOLOGY, WHICH INCLUDES EPIGENETIC CHROMATIN CHANGES COUPLED WITH CHANGES TO THE TRANSCRIPTOME AND SPLICING PATTERNS OF KEY GENES. 2015 6 2317 24 EPIGENETIC REGULATION OF G PROTEIN COUPLED RECEPTOR SIGNALING AND ITS IMPLICATIONS IN PSYCHIATRIC DISORDERS. G PROTEIN-COUPLED RECEPTORS (GPCRS) ACT AS A RELAY CENTER THROUGH WHICH EXTRACELLULAR SIGNALS, IN THE FORM OF NEUROTRANSMITTERS OR THERAPEUTICS, ARE CONVERTED INTO AN INTRACELLULAR RESPONSE, WHICH ULTIMATELY SHAPES THE OVERALL RESPONSE AT THE TISSUE AND BEHAVIORAL LEVEL. REMARKABLY IN SIMILAR WAYS, EPIGENETIC MECHANISMS ALSO MODULATE THE EXPRESSION PATTERN OF A LARGE NUMBER OF GENES IN RESPONSE TO THE DYNAMIC ENVIRONMENT INSIDE AND OUTSIDE OF THE BODY, AND CONSEQUENTLY OVERALL RESPONSE. EMERGING EVIDENCES FROM THE PHARMACOGENOMICS AND PRECLINICAL STUDIES CLEARLY SUGGEST THAT THESE TWO DISTINCT MECHANISMS CRISS-CROSS EACH OTHER IN SEVERAL NEUROLOGICAL DISORDERS. AT ONE HAND SUCH CROSS-TALKS BETWEEN TWO DISTINCT MECHANISMS MAKE DISEASE ETIOLOGY MORE CHALLENGING TO UNDERSTAND, WHILE ON THE OTHER HAND IF DEALT APPROPRIATELY, SUCH SITUATIONS MIGHT PROVIDE AN OPPORTUNITY TO FIND NOVEL DRUGGABLE TARGET AND STRATEGY FOR THE TREATMENT OF COMPLEX DISEASES. IN THIS REVIEW ARTICLE, WE HAVE SUMMARIZED AND HIGHLIGHTED THE MAIN FINDINGS THAT TIE EPIGENETIC MECHANISMS TO GPCR MEDIATED SIGNALING IN THE PATHOPHYSIOLOGY OF CENTRAL NERVOUS SYSTEM (CNS) DISORDERS, INCLUDING DEPRESSION, ADDICTION AND PAIN. 2016 7 3375 20 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 8 862 31 CHROMATIN REMODELING IN MONOCYTE AND MACROPHAGE ACTIVATION. INCREASING EVIDENCE COLLECTED DURING THE LAST YEARS SUPPORTS THE IDEA THAT MONOCYTE AND MACROPHAGE ACTIVATION IS NOT ONLY ASSOCIATED WITH TRANSCRIPTIONAL CHANGES BUT ALSO CHANGES IN THE CHROMATIN LANDSCAPE. MOREOVER, THE INTRODUCTION OF A MULTIDIMENSIONAL MODEL OF MACROPHAGE ACTIVATION ALLOWS A MORE PRECISE DESCRIPTION OF MONOCYTES AND MACROPHAGES UNDER HOMEOSTATIC AND PATHOPHYSIOLOGICAL CONDITIONS. MONOCYTES AND MACROPHAGES ARE MASTERS OF INTEGRATING MICROENVIRONMENTAL SIGNALS, THEREBY RESHAPING THEIR CHROMATIN LANDSCAPE AND AS A CONSEQUENCE THEIR TRANSCRIPTIONAL AND FUNCTIONAL PROGRAMS. ALBEIT THESE CELLS SHARE A LARGE NUMBER OF EPIGENETIC LANDMARKS, THEIR CHROMATIN IS SIGNIFICANTLY SHAPED BY ENVIRONMENTAL SIGNALS. THE CHROMATIN LANDSCAPE OF ANY GIVEN TISSUE MACROPHAGE IS A RATHER SPECIFIC FINGERPRINT OF THESE CELLS, WHICH IS DIRECTLY LINKED TO TISSUE-SPECIFIC FUNCTIONS OF THESE CELLS. MOREOVER, CHROMATIN REMODELING IN RESPONSE TO STRESS SIGNALS ALSO SEEMS TO BE AN IMPORTANT MECHANISM OF THESE CELLS TO INCREASE THEIR READINESS FOR FUTURE STRESSORS. UNDERSTANDING THIS SOPHISTICATED EPIGENETIC REGULATORY NETWORK IN MONOCYTES AND MACROPHAGES WILL OPEN UP NEW AVENUES TOWARD TISSUE- AND DISEASE-SPECIFIC THERAPEUTIC STRATEGIES IN MANY OF THE CHRONIC INFLAMMATORY DISEASES OUR SOCIETIES ARE CURRENTLY FACING. 2017 9 3952 21 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 10 2398 17 EPIGENETIC REPROGRAMMING OF CORTICAL NEURONS THROUGH ALTERATION OF DOPAMINERGIC CIRCUITS. ALTERATIONS OF THE DOPAMINERGIC SYSTEM ARE ASSOCIATED WITH THE COGNITIVE AND FUNCTIONAL DYSFUNCTIONS THAT CHARACTERIZE COMPLEX NEUROPSYCHIATRIC DISORDERS. WE MODELED A DYSFUNCTIONAL DOPAMINERGIC SYSTEM USING MICE WITH TARGETED ABLATION OF DOPAMINE (DA) D2 AUTORECEPTORS IN MESENCEPHALIC DOPAMINERGIC NEURONS. LOSS OF D2 AUTORECEPTORS ABOLISHES D2-MEDIATED CONTROL OF DA SYNTHESIS AND RELEASE. HERE, WE SHOW THAT THIS MUTATION LEADS TO A PROFOUND ALTERATION OF THE GENOMIC LANDSCAPE OF NEURONS RECEIVING DOPAMINERGIC AFFERENTS AT DISTAL SITES, SPECIFICALLY IN THE PREFRONTAL CORTEX. INDEED, WE OBSERVED A REMARKABLE DOWNREGULATION OF GENE EXPRESSION IN THIS AREA OF ~2000 GENES, WHICH INVOLVES A WIDESPREAD INCREASE IN THE HISTONE REPRESSIVE MARK H3K9ME2/3. THIS REPROGRAMMING PROCESS IS COUPLED TO PSYCHOTIC-LIKE BEHAVIORS IN THE MUTANT MICE. IMPORTANTLY, CHRONIC TREATMENT WITH A DA AGONIST CAN REVERT THE GENOMIC PHENOTYPE. THUS, CORTICAL NEURONS UNDERGO A PROFOUND EPIGENETIC REPROGRAMMING IN RESPONSE TO DYSFUNCTIONAL D2 AUTORECEPTOR SIGNALING LEADING TO ALTERED DA LEVELS, A PROCESS THAT MAY UNDERLIE A NUMBER OF NEUROPSYCHIATRIC DISORDERS. 2014 11 883 29 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 12 4278 29 MICROGLIAL INNATE MEMORY AND EPIGENETIC REPROGRAMMING IN NEUROLOGICAL DISORDERS. MICROGLIA ARE MYELOID-DERIVED CELLS RECOGNIZED AS BRAIN-RESIDENT MACROPHAGES. THEY ACT AS THE FIRST AND MAIN LINE OF IMMUNE DEFENSE IN THE CENTRAL NERVOUS SYSTEM (CNS). MICROGLIA HAVE HIGH PHENOTYPIC PLASTICITY AND ARE ESSENTIAL FOR REGULATING HEALTHY BRAIN HOMEOSTASIS, AND THEIR DYSREGULATION UNDERLIES THE ONSET AND PROGRESSION OF SEVERAL CNS PATHOLOGIES THROUGH IMPAIRED INFLAMMATORY RESPONSES. ABERRANT MICROGLIAL ACTIVATION, FOLLOWING AN INFLAMMATORY INSULT, IS ASSOCIATED WITH EPIGENETIC DYSREGULATION IN VARIOUS CNS PATHOLOGIES. EMERGING DATA SUGGEST THAT CERTAIN STIMULI TO MYELOID CELLS DETERMINE ENHANCED OR ATTENUATED RESPONSES TO SUBSEQUENT STIMULI. THESE PHENOMENA, GENERALLY TERMED INNATE IMMUNE MEMORY (IIM), ARE HIGHLY DEPENDENT ON EPIGENETIC REPROGRAMMING. MICROGLIAL PRIMING HAS BEEN REPORTED IN SEVERAL NEUROLOGICAL DISEASES AND CORRESPONDS TO A STATE OF INCREASED PERMISSIVENESS OR EXACERBATED RESPONSE, PROMOTED BY CONTINUOUS EXPOSURE TO A CHRONIC PRO-INFLAMMATORY ENVIRONMENT. IN THIS ARTICLE, WE PROVIDE EXTENSIVE EVIDENCE OF THESE EPIGENETIC-MEDIATED PHENOMENA UNDER NEUROLOGICAL CONDITIONS AND DISCUSS THEIR CONTRIBUTION TO PATHOGENESIS AND THEIR CLINICAL IMPLICATIONS, INCLUDING THOSE CONCERNING POTENTIAL NOVEL THERAPEUTIC APPROACHES. 2021 13 584 35 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 14 4620 20 NEURO-IMMUNE DYSFUNCTION DURING BRAIN AGING: NEW INSIGHTS IN MICROGLIAL CELL REGULATION. MICROGLIA, THE RESIDENT IMMUNE CELLS OF THE BRAIN, ARE AT THE CENTER OF COMMUNICATION BETWEEN THE CENTRAL NERVOUS SYSTEM AND IMMUNE SYSTEM. WHILE THESE BRAIN-IMMUNE INTERACTIONS ARE BALANCED IN HEALTHY ADULTHOOD, THE ABILITY TO MAINTAIN HOMEOSTASIS DURING AGING IS IMPAIRED. MICROGLIA DEVELOP A LOSS OF INTEGRATED REGULATORY NETWORKS INCLUDING ABERRANT SIGNALING FROM OTHER BRAIN CELLS, IMMUNE SENSORS, AND EPIGENETIC MODIFIERS. THE LOW-GRADE CHRONIC NEUROINFLAMMATION ASSOCIATED WITH THIS DYSFUNCTIONAL ACTIVITY LIKELY CONTRIBUTES TO COGNITIVE DEFICITS AND SUSCEPTIBILITY TO AGE-RELATED PATHOLOGIES. A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS RESPONSIBLE FOR NEURO-IMMUNE DYSREGULATION WITH AGE IS CRUCIAL FOR PROVIDING TARGETED THERAPEUTIC STRATEGIES TO SUPPORT BRAIN REPAIR AND HEALTHY AGING. 2016 15 6450 27 THERAPEUTIC TARGETS FOR INFLAMMATION-MEDIATED AIRWAY REMODELING IN CHRONIC LUNG DISEASE. ACUTE EXACERBATIONS OF CHRONIC LUNG DISEASE ACCOUNT FOR SUBSTANTIAL MORBIDITY AND HEALTH COSTS. REPEATED INFLAMMATORY EPISODES AND ATTENDANT BRONCHOCONSTRICTION CAUSE STRUCTURAL REMODELING OF THE AIRWAY. REMODELING IS A MULTICELLULAR RESPONSE TO MUCOSAL INJURY THAT RESULTS IN EPITHELIAL CELL-STATE CHANGES, ENHANCED EXTRACELLULAR DEPOSITION, AND EXPANSION OF PRO-FIBROTIC MYOFIBROBLAST POPULATIONS. AREAS COVERED: THIS MANUSCRIPT OVERVIEWS MECHANISTIC STUDIES IDENTIFYING KEY SENTINEL CELL POPULATIONS IN THE AIRWAY AND HOW PATTERN RECOGNITION SIGNALING INDUCES MALADAPTIVE MUCOSAL CHANGES AND AIRWAY REMODELING. STUDIES ELUCIDATING HOW NFKAPPAB COUPLES WITH AN ATYPICAL HISTONE ACETYLTRANSFERASE, BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) THAT REPROGRAMS MUCOSAL FIBROGENIC RESPONSES, ARE DESCRIBED. THE APPROACHES TO DEVELOPMENT AND CHARACTERIZATION OF SELECTIVE INHIBITORS OF EPIGENETIC REPROGRAMMING ON INNATE INFLAMMATION AND STRUCTURAL REMODELING IN PRECLINICAL MODELS ARE DETAILED. EXPERT COMMENTARY: BRONCHIOLAR CELLS DERIVED FROM SCGB1A1-EXPRESSING PROGENITORS FUNCTION AS MAJOR SENTINEL CELLS OF THE AIRWAY, RESPONSIBLE FOR INITIATING ANTIVIRAL AND AEROALLERGEN RESPONSES. IN THESE SENTINEL CELLS, ACTIVATION OF INNATE INFLAMMATION IS COUPLED TO NEUTROPHILIC RECRUITMENT, MESENCHYMAL TRANSITION AND MYOFIBROBLAST EXPANSION. THERAPEUTICS TARGETING THE NFKB-BRD4 MAY BE EFFICACIOUS IN REDUCING PATHOLOGICAL EFFECTS OF ACUTE EXACERBATIONS IN CHRONIC LUNG DISEASE. 2018 16 6621 28 UNDERSTANDING FIBROSIS IN SYSTEMIC SCLEROSIS: SHIFTING PARADIGMS, EMERGING OPPORTUNITIES. FIBROSIS IN MULTIPLE ORGANS IS A PROMINENT PATHOLOGICAL FINDING AND DISTINGUISHING HALLMARK OF SYSTEMIC SCLEROSIS (SSC). FINDINGS DURING THE PAST 5 YEARS HAVE CONTRIBUTED TO A MORE COMPLETE UNDERSTANDING OF THE COMPLEX CELLULAR AND MOLECULAR UNDERPINNING OF FIBROSIS IN SSC. FIBROBLASTS, THE PRINCIPAL EFFECTOR CELLS, ARE ACTIVATED IN THE PROFIBROTIC CELLULAR MILIEU BY CYTOKINES AND GROWTH FACTORS, DEVELOPMENTAL PATHWAYS, ENDOTHELIN 1 AND THROMBIN. INNATE IMMUNE SIGNALING VIA TOLL-LIKE RECEPTORS, MATRIX-GENERATED BIOMECHANICAL STRESS SIGNALING VIA INTEGRINS, HYPOXIA AND OXIDATIVE STRESS SEEM TO BE IMPLICATED IN PERPETUATING THE PROCESS. BEYOND CHRONIC FIBROBLAST ACTIVATION, FIBROSIS REPRESENTS A FAILURE TO TERMINATE TISSUE REPAIR, COUPLED WITH AN EXPANDED POPULATION OF MESENCHYMAL CELLS ORIGINATING FROM BONE MARROW AND TRANSDIFFERENTIATION OF EPITHELIAL CELLS, ENDOTHELIAL CELLS AND PERICYTES. IN ADDITION, STUDIES HAVE IDENTIFIED INTRINSIC ALTERATIONS IN SSC FIBROBLASTS RESULTING FROM EPIGENETIC CHANGES, AS WELL AS ALTERED MICRORNA EXPRESSION THAT MIGHT UNDERLIE THE CELL-AUTONOMOUS, PERSISTENT ACTIVATION PHENOTYPE OF THESE CELLS. PRECISE CHARACTERIZATION OF THE DEREGULATED EXTRACELLULAR AND INTRACELLULAR SIGNALING PATHWAYS, MEDIATORS AND CELLULAR DIFFERENTIATION PROGRAMS THAT CONTRIBUTE TO FIBROSIS IN SSC WILL FACILITATE THE DEVELOPMENT OF SELECTIVE, TARGETED THERAPEUTIC STRATEGIES. EFFECTIVE ANTIFIBROTIC THERAPY WILL ULTIMATELY INVOLVE NOVEL COMPOUNDS AND REPURPOSING OF DRUGS THAT ARE ALREADY APPROVED FOR OTHER INDICATIONS. 2011 17 6014 28 THE ARCHITECTURAL DESIGN OF CD8+ T CELL RESPONSES IN ACUTE AND CHRONIC INFECTION: PARALLEL STRUCTURES WITH DIVERGENT FATES. IN RESPONSE TO INFECTION, T CELLS ADOPT A RANGE OF DIFFERENTIATION STATES, CREATING NUMEROUS HETEROGENEOUS SUBSETS THAT EXHIBIT DIFFERENT PHENOTYPES, FUNCTIONS, AND MIGRATION PATTERNS. THIS T CELL HETEROGENEITY IS A UNIVERSAL FEATURE OF T CELL IMMUNITY, NEEDED TO EFFECTIVELY CONTROL PATHOGENS IN A CONTEXT-DEPENDENT MANNER AND GENERATE LONG-LIVED IMMUNITY TO THOSE PATHOGENS. HERE, WE REVIEW NEW INSIGHTS INTO DIFFERENTIATION STATE DYNAMICS AND POPULATION HETEROGENEITY OF CD8+ T CELLS IN ACUTE AND CHRONIC VIRAL INFECTIONS AND CANCER AND HIGHLIGHT THE PARALLELS AND DISTINCTIONS BETWEEN ACUTE AND CHRONIC ANTIGEN STIMULATION SETTINGS. WE FOCUS ON TRANSCRIPTIONAL AND EPIGENETIC NETWORKS THAT MODULATE THE PLASTICITY AND TERMINAL DIFFERENTIATION OF ANTIGEN-SPECIFIC CD8+ T CELLS AND GENERATE FUNCTIONALLY DIVERSE T CELL SUBSETS WITH DIFFERENT ROLES TO COMBAT INFECTION AND CANCER. 2021 18 3395 31 HOST GENETIC FACTORS PREDISPOSING TO HIV-ASSOCIATED NEUROCOGNITIVE DISORDER. THE SUCCESS OF COMBINATION ANTIRETROVIRAL THERAPY (CART) IN TRANSFORMING THE LIVES OF HIV-INFECTED INDIVIDUALS WITH ACCESS TO THESE DRUGS IS TEMPERED BY THE INCREASING THREAT OF HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS (HAND) TO THEIR OVERALL HEALTH AND QUALITY OF LIFE. INTENSIVE INVESTIGATIONS OVER THE PAST TWO DECADES HAVE UNDERSCORED THE ROLE OF HOST IMMUNE RESPONSES, INFLAMMATION, AND MONOCYTE-DERIVED MACROPHAGES IN HAND, BUT THE PRECISE PATHOGENIC MECHANISMS UNDERLYING HAND REMAIN ONLY PARTIALLY DELINEATED. COMPLICATING RESEARCH EFFORTS AND THERAPEUTIC DRUG DEVELOPMENT ARE THE SHEER COMPLEXITY OF HAND PHENOTYPES, DIAGNOSTIC IMPRECISION, AND THE GROWING INTERSECTION OF CHRONIC IMMUNE ACTIVATION WITH AGING-RELATED COMORBIDITIES. YET, GENETIC STUDIES STILL OFFER A POWERFUL MEANS OF ADVANCING INDIVIDUALIZED CARE FOR HIV-INFECTED INDIVIDUALS AT RISK. THERE IS AN URGENT NEED FOR 1) LONGITUDINAL STUDIES USING CONSISTENT PHENOTYPIC DEFINITIONS OF HAND IN HIV-INFECTED SUBPOPULATIONS AT VERY HIGH RISK OF BEING ADVERSELY IMPACTED, SUCH AS CHILDREN, 2) TISSUE STUDIES THAT CORRELATE NEUROPATHOLOGICAL CHANGES IN MULTIPLE BRAIN REGIONS WITH GENOMIC MARKERS IN AFFECTED INDIVIDUALS AND WITH CHANGES AT THE RNA, EPIGENOMIC, AND/OR PROTEIN LEVELS, AND 3) GENETIC ASSOCIATION STUDIES USING MORE SENSITIVE SUBPHENOTYPES OF HAND. THE NIH BRAIN INITIATIVE AND HUMAN CONNECTOME PROJECT, COUPLED WITH RAPIDLY EVOLVING SYSTEMS BIOLOGY AND MACHINE LEARNING APPROACHES FOR ANALYZING HIGH-THROUGHPUT GENETIC, TRANSCRIPTOMIC AND EPIGENETIC DATA, HOLD PROMISE FOR IDENTIFYING ACTIONABLE BIOLOGICAL PROCESSES AND GENE NETWORKS THAT UNDERLIE HAND. THIS REVIEW SUMMARIZES THE CURRENT STATE OF UNDERSTANDING OF HOST GENETIC FACTORS PREDISPOSING TO HAND IN LIGHT OF PAST CHALLENGES AND SUGGESTS SOME PRIORITIES FOR FUTURE RESEARCH TO ADVANCE THE UNDERSTANDING AND CLINICAL MANAGEMENT OF HAND IN THE CART ERA. 2014 19 3949 33 LNCRNAS IN T LYMPHOCYTES: RNA REGULATION AT THE HEART OF THE IMMUNE RESPONSE. GENOME-WIDE ANALYSES IN THE LAST DECADE HAVE UNCOVERED THE PRESENCE OF A LARGE NUMBER OF LONG NON-PROTEIN-CODING TRANSCRIPTS THAT SHOW HIGHLY TISSUE- AND STATE-SPECIFIC EXPRESSION PATTERNS. HIGH-THROUGHPUT SEQUENCING ANALYSES IN DIVERSE SUBSETS OF IMMUNE CELLS HAVE REVEALED A COMPLEX AND DYNAMIC EXPRESSION PATTERN FOR THESE LONG NONCODING RNAS (LNCRNAS) THAT CORRELATE WITH THE FUNCTIONAL STATES OF IMMUNE CELLS. ALTHOUGH THE VAST MAJORITY OF LNCRNAS EXPRESSED IN IMMUNE CELLS REMAIN UNSTUDIED, FUNCTIONAL STUDIES PERFORMED ON A SMALL SUBSET HAVE INDICATED THAT THEIR STATE-SPECIFIC EXPRESSIONS PATTERN FREQUENTLY HAS A REGULATORY IMPACT ON THE FUNCTION OF IMMUNE CELLS. IN VIVO AND IN VITRO STUDIES HAVE POINTED TO THE INVOLVEMENT OF LNCRNAS IN A WIDE VARIETY OF CELLULAR PROCESSES, INCLUDING BOTH THE INNATE AND ADAPTIVE IMMUNE RESPONSE THROUGH MECHANISMS RANGING FROM EPIGENETIC AND TRANSCRIPTIONAL REGULATION TO SEQUESTRATION OF FUNCTIONAL MOLECULES IN SUBCELLULAR COMPARTMENTS. THIS REVIEW WILL FOCUS MAINLY ON THE ROLE OF LNCRNAS IN CD4(+) AND CD8(+) T CELLS, WHICH PLAY PIVOTAL ROLES IN ADAPTIVE IMMUNITY. RECENT STUDIES HAVE POINTED TO KEY PHYSIOLOGICAL FUNCTIONS FOR LNCRNAS DURING SEVERAL DEVELOPMENTAL AND FUNCTIONAL STAGES OF THE LIFE CYCLE OF LYMPHOCYTES. ALTHOUGH LNCRNAS PLAY IMPORTANT PHYSIOLOGICAL ROLES IN LYMPHOCYTIC RESPONSE TO ANTIGENIC STIMULATION, DIFFERENTIATION INTO EFFECTOR CELLS, AND SECRETION OF CYTOKINES, THEIR DYSREGULATED EXPRESSION CAN PROMOTE OR SUSTAIN PATHOLOGICAL STATES SUCH AS AUTOIMMUNITY, CHRONIC INFLAMMATION, CANCER, AND VIREMIA. THIS, TOGETHER WITH THEIR HIGHLY CELL TYPE-SPECIFIC EXPRESSION PATTERNS, MAKES LNCRNAS IDEAL THERAPEUTIC TARGETS AND UNDERSCORES THE NEED FOR ADDITIONAL STUDIES INTO THE ROLE OF THESE UNDERSTUDIED TRANSCRIPTS IN ADAPTIVE IMMUNE RESPONSE. 2021 20 5415 30 REGULATION OF CELLULAR IMMUNE RESPONSES IN SEPSIS BY HISTONE MODIFICATIONS. SEVERE SEPSIS, SEPTIC SHOCK, AND RELATED INFLAMMATORY SYNDROMES ARE DRIVEN BY THE ABERRANT EXPRESSION OF PROINFLAMMATORY MEDIATORS BY IMMUNE CELLS. DURING THE ACUTE PHASE OF SEPSIS, OVEREXPRESSION OF CHEMOKINES AND CYTOKINES DRIVES PHYSIOLOGICAL STRESS LEADING TO ORGAN FAILURE AND MORTALITY. FOLLOWING RECOVERY FROM SEPSIS, THE IMMUNE SYSTEM EXHIBITS PROFOUND IMMUNOSUPPRESSION, EVIDENCED BY AN INABILITY TO PRODUCE THE SAME PROINFLAMMATORY MEDIATORS THAT ARE REQUIRED FOR NORMAL RESPONSES TO INFECTIOUS MICROORGANISMS. GENE EXPRESSION IN INFLAMMATORY RESPONSES IS INFLUENCED BY THE TRANSCRIPTIONAL ACCESSIBILITY OF THE CHROMATIN, WITH HISTONE POSTTRANSLATIONAL MODIFICATIONS DETERMINING WHETHER INFLAMMATORY GENE LOCI ARE SET TO TRANSCRIPTIONALLY ACTIVE, REPRESSED, OR POISED STATES. EXPERIMENTAL EVIDENCE INDICATES THAT HISTONE MODIFICATIONS PLAY A CENTRAL ROLE IN GOVERNING THE CYTOKINE STORM OF SEVERE SEPSIS, AND THAT ABERRANT CHROMATIN MODIFICATIONS INDUCED DURING THE ACUTE PHASE OF SEPSIS MAY MEDIATE CHRONIC IMMUNOSUPPRESSION IN SEPSIS SURVIVORS. THIS REVIEW WILL FOCUS ON THE ROLE OF HISTONE MODIFICATIONS IN GOVERNING IMMUNE RESPONSES IN SEVERE SEPSIS, WITH AN EMPHASIS ON SPECIFIC LEUKOCYTE SUBSETS AND THE HISTONE MODIFICATIONS OBSERVED IN THESE CELLS DURING CHRONIC STAGES OF SEPSIS. ADDITIONALLY, THE EXPRESSION AND FUNCTION OF CHROMATIN-MODIFYING ENZYMES (CMES) WILL BE DISCUSSED IN THE CONTEXT OF SEVERE SEPSIS, AS POTENTIAL MEDIATORS OF EPIGENETIC REGULATION OF GENE EXPRESSION IN SEPSIS RESPONSES. IN SUMMARY, THIS REVIEW WILL ARGUE FOR THE USE OF CHROMATIN MODIFICATIONS AND CME EXPRESSION IN LEUKOCYTES AS POTENTIAL BIOMARKERS OF IMMUNOSUPPRESSION IN PATIENTS WITH SEVERE SEPSIS. 2017