1 4384 116 MITOCHONDRIAL EPIGENETICS REGULATING INFLAMMATION IN CANCER AND AGING. INFLAMMATION IS A DEFINING FACTOR IN DISEASE PROGRESSION; EPIGENETIC MODIFICATIONS OF THIS FIRST LINE OF DEFENCE PATHWAY CAN AFFECT MANY PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS, LIKE AGING AND TUMORIGENESIS. INFLAMMAGEING, ONE OF THE HALLMARKS OF AGING, REPRESENTS A CHRONIC, LOW KEY BUT A PERSISTENT INFLAMMATORY STATE. OXIDATIVE STRESS, ALTERATIONS IN MITOCHONDRIAL DNA (MTDNA) COPY NUMBER AND MIS-LOCALIZED EXTRA-MITOCHONDRIAL MTDNA ARE SUGGESTED TO DIRECTLY INDUCE VARIOUS IMMUNE RESPONSE PATHWAYS. THIS COULD ULTIMATELY PERTURB CELLULAR HOMEOSTASIS AND LEAD TO PATHOLOGICAL CONSEQUENCES. EPIGENETIC REMODELLING OF MTDNA BY DNA METHYLATION, POST-TRANSLATIONAL MODIFICATIONS OF MTDNA BINDING PROTEINS AND REGULATION OF MITOCHONDRIAL GENE EXPRESSION BY NUCLEAR DNA OR MTDNA ENCODED NON-CODING RNAS, ARE SUGGESTED TO DIRECTLY CORRELATE WITH THE ONSET AND PROGRESSION OF VARIOUS TYPES OF CANCER. MITOCHONDRIA ARE ALSO CAPABLE OF REGULATING IMMUNE RESPONSE TO VARIOUS INFECTIONS AND TISSUE DAMAGE BY PRODUCING PRO- OR ANTI-INFLAMMATORY SIGNALS. THIS OCCURS BY ALTERING THE LEVELS OF MITOCHONDRIAL METABOLITES AND REACTIVE OXYGEN SPECIES (ROS) LEVELS. SINCE MITOCHONDRIA ARE KNOWN AS THE GUARDIANS OF THE INFLAMMATORY RESPONSE, IT IS PLAUSIBLE THAT MITOCHONDRIAL EPIGENETICS MIGHT PLAY A PIVOTAL ROLE IN INFLAMMATION. HENCE, THIS REVIEW FOCUSES ON THE INTRICATE DYNAMICS OF EPIGENETIC ALTERATIONS OF INFLAMMATION, WITH EMPHASIS ON MITOCHONDRIA IN CANCER AND AGING. 2022 2 1855 29 ELEVATION IN S-ADENOSYLHOMOCYSTEINE AND DNA HYPOMETHYLATION: POTENTIAL EPIGENETIC MECHANISM FOR HOMOCYSTEINE-RELATED PATHOLOGY. CHRONIC NUTRITIONAL DEFICIENCIES IN FOLATE, CHOLINE, METHIONINE, VITAMIN B-6 AND/OR VITAMIN B-12 CAN PERTURB THE COMPLEX REGULATORY NETWORK THAT MAINTAINS NORMAL ONE-CARBON METABOLISM AND HOMOCYSTEINE HOMEOSTASIS. GENETIC POLYMORPHISMS IN THESE PATHWAYS CAN ACT SYNERGISTICALLY WITH NUTRITIONAL DEFICIENCIES TO ACCELERATE METABOLIC PATHOLOGY ASSOCIATED WITH OCCLUSIVE HEART DISEASE, BIRTH DEFECTS AND DEMENTIA. A MAJOR UNANSWERED QUESTION IS WHETHER HOMOCYSTEINE IS CAUSALLY INVOLVED IN DISEASE PATHOGENESIS OR WHETHER HOMOCYSTEINEMIA IS SIMPLY A PASSIVE AND INDIRECT INDICATOR OF A MORE COMPLEX MECHANISM. S-ADENOSYLMETHIONINE AND S-ADENOSYLHOMOCYSTEINE (SAH), AS THE SUBSTRATE AND PRODUCT OF METHYLTRANSFERASE REACTIONS, ARE IMPORTANT METABOLIC INDICATORS OF CELLULAR METHYLATION STATUS. CHRONIC ELEVATION IN HOMOCYSTEINE LEVELS RESULTS IN PARALLEL INCREASES IN INTRACELLULAR SAH AND POTENT PRODUCT INHIBITION OF DNA METHYLTRANSFERASES. SAH-MEDIATED DNA HYPOMETHYLATION AND ASSOCIATED ALTERATIONS IN GENE EXPRESSION AND CHROMATIN STRUCTURE MAY PROVIDE NEW HYPOTHESES FOR PATHOGENESIS OF DISEASES RELATED TO HOMOCYSTEINEMIA. 2002 3 1623 31 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 4 64 30 A HIGH-THROUGHPUT SCREENING ASSAY FOR SILENCING ESTABLISHED HIV-1 MACROPHAGE INFECTION IDENTIFIES NUCLEOSIDE ANALOGS THAT PERTURB H3K9ME3 ON PROVIRAL GENOMES. HIV-INFECTED MACROPHAGES ARE LONG-LIVED CELLS THAT REPRESENT A BARRIER TO FUNCTIONAL CURE. ADDITIONALLY, LOW-LEVEL VIRAL EXPRESSION BY CENTRAL NERVOUS SYSTEM (CNS) MACROPHAGES CONTRIBUTES TO NEUROCOGNITIVE DEFICITS THAT DEVELOP DESPITE ANTIRETROVIRAL THERAPY (ART). WE RECENTLY IDENTIFIED H3K9ME3 AS AN ATYPICAL EPIGENETIC MARK ASSOCIATED WITH CHRONIC HIV INFECTION IN MACROPHAGES. THUS, STRATEGIES ARE NEEDED TO SUPPRESS HIV-1 EXPRESSION IN MACROPHAGES, BUT THE UNIQUE MYELOID ENVIRONMENT AND THE RESPONSIBLE MACROPHAGE/CNS-TROPIC STRAINS REQUIRE CELL/STRAIN-SPECIFIC APPROACHES. HERE, WE GENERATED AN HIV-1 REPORTER VIRUS FROM A CNS-DERIVED STRAIN WITH INTACT AUXILIARY GENES EXPRESSING DESTABILIZED LUCIFERASE. WE EMPLOYED THIS REPORTER VIRUS IN POLYCLONAL INFECTION OF PRIMARY HUMAN MONOCYTE-DERIVED MACROPHAGES (MDM) FOR A HIGH-THROUGHPUT SCREEN (HTS) TO IDENTIFY COMPOUNDS THAT SUPPRESS VIRUS EXPRESSION FROM ESTABLISHED MACROPHAGE INFECTION. SCREENING ~6,000 KNOWN DRUGS AND COMPOUNDS YIELDED 214 HITS. A SECONDARY SCREEN WITH 10-DOSE TITRATION IDENTIFIED 24 MEETING CRITERIA FOR HIV-SELECTIVE ACTIVITY. USING THREE REPLICATION-COMPETENT CNS-DERIVED MACROPHAGE-TROPIC HIV-1 ISOLATES AND VIRAL GENE EXPRESSION READOUT IN MDM, WE CONFIRMED THE EFFECT OF THREE PURINE ANALOGS, NELARABINE, FLUDARABINE, AND ENTECAVIR, SHOWING THE SUPPRESSION OF HIV-1 EXPRESSION FROM ESTABLISHED MACROPHAGE INFECTION. NELARABINE INHIBITED THE FORMATION OF H3K9ME3 ON HIV GENOMES IN MACROPHAGES. THUS, THIS NOVEL HTS ASSAY CAN IDENTIFY SUPPRESSORS OF HIV-1 TRANSCRIPTION IN ESTABLISHED MACROPHAGE INFECTION, SUCH AS NUCLEOSIDE ANALOGS AND HDAC INHIBITORS, WHICH MAY BE LINKED TO H3K9ME3 MODIFICATION. THIS SCREEN MAY BE USEFUL TO IDENTIFY NEW METABOLIC AND EPIGENETIC AGENTS THAT AMELIORATE HIV-DRIVEN NEUROINFLAMMATION IN PEOPLE ON ART OR PREVENT VIRAL RECRUDESCENCE FROM MACROPHAGE RESERVOIRS IN STRATEGIES TO ACHIEVE ART-FREE REMISSION. IMPORTANCE MACROPHAGES INFECTED BY HIV-1 ARE A LONG-LIVED RESERVOIR AND A BARRIER IN CURRENT EFFORTS TO ACHIEVE HIV CURE AND ALSO CONTRIBUTE TO NEUROCOGNITIVE COMPLICATIONS IN PEOPLE DESPITE ANTIRETROVIRAL THERAPY (ART). SILENCING HIV EXPRESSION IN THESE CELLS WOULD BE OF GREAT VALUE, BUT THE REGULATION OF HIV-1 IN MACROPHAGES DIFFERS FROM T CELLS. WE DEVELOPED A NOVEL HIGH-THROUGHPUT SCREEN FOR COMPOUNDS THAT CAN SILENCE ESTABLISHED INFECTION OF PRIMARY MACROPHAGES, AND IDENTIFIED AGENTS THAT DOWNREGULATE VIRUS EXPRESSION AND ALTER PROVIRUS EPIGENETIC PROFILES. THE SIGNIFICANCE OF THIS ASSAY IS THE POTENTIAL TO IDENTIFY NEW DRUGS THAT ACT IN THE UNIQUE MACROPHAGE ENVIRONMENT ON RELEVANT VIRAL STRAINS, WHICH MAY CONTRIBUTE TO ADJUNCTIVE TREATMENT FOR HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS AND/OR PREVENT VIRAL REBOUND IN EFFORTS TO ACHIEVE ART-FREE REMISSION OR CURE. 2023 5 4124 28 MECHANISMS OF DISEASE PROGRESSION AND RESISTANCE TO TYROSINE KINASE INHIBITOR THERAPY IN CHRONIC MYELOID LEUKEMIA: AN UPDATE. CHRONIC MYELOID LEUKEMIA (CML) IS CHARACTERIZED BY THE PRESENCE OF THE BCR-ABL1 FUSION GENE, WHICH ENCODES A CONSTITUTIVE ACTIVE TYROSINE KINASE CONSIDERED TO BE THE PATHOGENIC DRIVER CAPABLE OF INITIATING AND MAINTAINING THE DISEASE. DESPITE THE REMARKABLE EFFICACY OF TYROSINE KINASE INHIBITORS (TKIS) TARGETING BCR-ABL1, SOME PATIENTS MAY NOT RESPOND (PRIMARY RESISTANCE) OR MAY RELAPSE AFTER AN INITIAL RESPONSE (SECONDARY RESISTANCE). IN A SMALL PROPORTION OF CASES, DEVELOPMENT OF RESISTANCE IS ACCOMPANIED OR SHORTLY FOLLOWED BY PROGRESSION FROM CHRONIC TO BLASTIC PHASE (BP), CHARACTERIZED BY A DISMAL PROGNOSIS. EVOLUTION FROM CP INTO BP IS A MULTIFACTORIAL AND PROBABLY MULTISTEP PHENOMENON. INCREASE IN BCR-ABL1 TRANSCRIPT LEVELS IS THOUGHT TO PROMOTE THE ONSET OF SECONDARY CHROMOSOMAL OR GENETIC DEFECTS, INDUCE DIFFERENTIATION ARREST, PERTURB RNA TRANSCRIPTION, EDITING AND TRANSLATION THAT TOGETHER WITH EPIGENETIC AND METABOLIC CHANGES MAY ULTIMATELY LEAD TO THE EXPANSION OF HIGHLY PROLIFERATING, DIFFERENTIATION-ARRESTED MALIGNANT CELLS. A MULTITUDE OF STUDIES OVER THE PAST TWO DECADES HAVE INVESTIGATED THE MECHANISMS UNDERLYING THE CLOSELY INTERTWINED PHENOMENA OF DRUG RESISTANCE AND DISEASE PROGRESSION. HERE, WE PROVIDE AN UPDATE ON WHAT IS CURRENTLY KNOWN ON THE MECHANISMS UNDERLYING PROGRESSION AND PRESENT THE LATEST ACQUISITIONS ON BCR-ABL1-INDEPENDENT RESISTANCE AND LEUKEMIA STEM CELL PERSISTENCE. 2019 6 6755 25 WILL WIDESPREAD SYNTHETIC OPIOID CONSUMPTION INDUCE EPIGENETIC CONSEQUENCES IN FUTURE GENERATIONS? A GROWING NUMBER OF EVIDENCE DEMONSTRATES THAT ANCESTRAL EXPOSURE TO XENOBIOTICS (POLLUTANTS, DRUGS OF ABUSE, ETC.) CAN PERTURB THE PHYSIOLOGY AND BEHAVIOR OF DESCENDANTS. BOTH MATERNAL AND PATERNAL TRANSMISSION OF PHENOTYPE ACROSS GENERATIONS HAS BEEN PROVED, DEMONSTRATING THAT PARENTAL DRUG HISTORY MAY HAVE SIGNIFICANT IMPLICATIONS FOR SUBSEQUENT GENERATIONS. IN THE LAST YEARS, THE BURDEN OF NOVEL SYNTHETIC OPIOID (NSO) CONSUMPTION, DUE TO INCREASED MEDICAL PRESCRIPTION OF PAIN MEDICATIONS AND TO EASIER ACCESSIBILITY OF THESE SUBSTANCES ON ILLEGAL MARKET, IS RAISING NEW QUESTIONS FIRST IN TERM OF PUBLIC HEALTH, BUT ALSO ABOUT THE CONSEQUENCES OF THE PARENTAL USE OF THESE DRUGS ON FUTURE GENERATIONS. BESIDES BEING ASSOCIATED TO THE NEONATAL ABSTINENCE SYNDROME, IN UTERO EXPOSURE TO OPIOIDS HAS AN IMPACT ON NEURONAL DEVELOPMENT WITH LONG-TERM REPERCUSSIONS THAT ARE POTENTIALLY TRANSMITTED TO SUBSEQUENT GENERATIONS. IN ADDITION, RECENT REPORTS SUGGEST THAT OPIOID USE EVEN BEFORE CONCEPTION INFLUENCES THE REACTIVITY TO OPIOIDS OF THE PROGENY AND THE FOLLOWING GENERATIONS, LIKELY THROUGH EPIGENETIC MECHANISMS. THIS REVIEW DESCRIBES THE CURRENT KNOWLEDGE ABOUT THE TRANSGENERATIONAL EFFECTS OF OPIOID CONSUMPTION. WE SUMMARIZE THE PRECLINICAL AND CLINICAL FINDINGS SHOWING THE IMPLICATIONS FOR THE SUBSEQUENT GENERATIONS OF PARENTAL EXPOSURE TO OPIOIDS EARLIER IN LIFE. LIMITATIONS OF THE EXISTING DATA ON NSOS AND NEW PERSPECTIVES OF THE RESEARCH ARE ALSO DISCUSSED, AS WELL AS CLINICAL AND FORENSIC CONSEQUENCES. 2018 7 6083 30 THE EFFECT OF SMOKING ON DNA METHYLATION OF PERIPHERAL BLOOD MONONUCLEAR CELLS FROM AFRICAN AMERICAN WOMEN. BACKGROUND: REGULAR SMOKING IS ASSOCIATED WITH A WIDE VARIETY OF SYNDROMES WITH PROMINENT INFLAMMATORY COMPONENTS SUCH AS CANCER, OBESITY AND TYPE 2 DIABETES. HEAVY REGULAR SMOKING IS ALSO ASSOCIATED WITH CHANGES IN THE DNA METHYLATION OF PERIPHERAL MONONUCLEAR CELLS. HOWEVER, IN YOUNGER SMOKERS, INFLAMMATORY EPIGENETIC FINDINGS ARE LARGELY ABSENT WHICH SUGGESTS THE INFLAMMATORY RESPONSE(S) TO SMOKING MAY BE DOSE DEPENDENT. TO HELP UNDERSTAND WHETHER PERIPHERAL MONONUCLEAR CELLS HAVE A ROLE IN MEDIATING THESE RESPONSES IN OLDER SMOKERS WITH HIGHER CUMULATIVE SMOKE EXPOSURE, WE EXAMINED GENOME-WIDE DNA METHYLATION IN A GROUP OF WELL CHARACTERIZED ADULT AFRICAN AMERICAN SUBJECTS INFORMATIVE FOR SMOKING, AS WELL AS SERUM C-REACTIVE PROTEIN (CRP) AND INTERLEUKIN-6 RECEPTOR (IL6R) LEVELS. IN ADDITION, COMPLEMENTARY BIOINFORMATIC ANALYSES WERE CONDUCTED TO DELINEATE POSSIBLE PATHWAYS AFFECTED BY LONG-TERM SMOKING. RESULTS: GENOME-WIDE DNA METHYLATION ANALYSIS WITH RESPECT TO SMOKING STATUS YIELDED 910 SIGNIFICANT LOCI AFTER BENJAMINI-HOCHBERG CORRECTION. IN PARTICULAR, TWO LOCI FROM THE AHRR GENE (CG05575921 AND CG23576855) AND ONE LOCUS FROM THE GPR15 GENE (CG19859270) WERE IDENTIFIED AS HIGHLY SIGNIFICANTLY DIFFERENTIALLY METHYLATED BETWEEN SMOKERS AND NON-SMOKERS. THE BIOINFORMATIC ANALYSES SHOWED THAT LONG-TERM CHRONIC SMOKING IS ASSOCIATED WITH ALTERED PROMOTER DNA METHYLATION OF GENES CODING FOR PROTEINS MAPPING TO CRITICAL SUB-NETWORKS MODERATING INFLAMMATION, IMMUNE FUNCTION, AND COAGULATION. CONCLUSIONS: WE CONCLUDE THAT CHRONIC REGULAR SMOKING IS ASSOCIATED WITH CHANGES IN PERIPHERAL MONONUCLEAR CELL METHYLATION SIGNATURE WHICH PERTURB INFLAMMATORY AND IMMUNE FUNCTION PATHWAYS AND MAY CONTRIBUTE TO INCREASED VULNERABILITY FOR COMPLEX ILLNESSES WITH INFLAMMATORY COMPONENTS. 2014 8 5362 26 RECENT ADVANCES IN CALORIE RESTRICTION RESEARCH ON AGING. THE EXTENSION OF BOTH MEDIAN AND MAXIMUM LIFESPAN AND THE SUPPRESSION OF AGE-RELATED DISEASES IN LABORATORY ANIMALS BY REDUCED FOOD INTAKE, I.E., CALORIE RESTRICTION (CR) ARE REGARDED AS HALLMARKS OF CR'S ANTI-AGING ACTION. THE DIVERSE EFFICACY OF CR TO COUNTERACT AGING EFFECTS AND ITS EXPERIMENTAL REPRODUCIBILITY HAS MADE IT THE GOLD STANDARD OF MANY AGING INTERVENTION STUDIES OF RECENT YEARS. ALTHOUGH CR ORIGINALLY WAS USED AS A TOOL TO PERTURB THE AGING PROCESS OF LABORATORY ANIMALS AS TO UNCOVER CLUES OF UNDERLYING MECHANISMS OF AGING PROCESSES, CURRENT CR RESEARCH INTERESTS HAVE SHIFTED TO THE RETARDATION OF AGING-RELATED FUNCTIONAL DECLINE AND THE PREVENTION OF AGE-RELATED DISEASES. ADVANCES IN CR RESEARCH ON NON-HUMAN PRIMATES AND RECENT ENDEAVORS USING HUMAN SUBJECTS OFFER A PROMISING OUTLOOK FOR CR'S BENEFICIAL EFFECTS IN HEALTHY HUMAN AGING. IN THIS REVIEW, SEVERAL MAJOR ISSUES RELATED TO CR'S ANTI-AGING MECHANISMS ARE DISCUSSED BY HIGHLIGHTING THE IMPORTANCE OF MODULATING DELETERIOUS CHRONIC INFLAMMATION AT MOLECULAR LEVELS AND THE IMPACT OF EPIGENETIC CHROMATIN AND HISTONE MODIFICATIONS BY CR AT THE ULTIMATE CONTROL SITES OF GENE EXPRESSION. THE RECENT RESEARCH ON RAPAMYCIN AS A CR MIMETIC IS SUMMARIZED AND A BRIEF DESCRIPTION OF INTERMITTENT FEEDING PATTERNS IS REVIEWED IN COMPARISON TO THE CR EFFECT. 2013 9 4383 36 MITOCHONDRIAL EPIGENETICS AND ENVIRONMENTAL HEALTH: MAKING A CASE FOR ENDOCRINE DISRUPTING CHEMICALS. RECENT STUDIES IMPLICATE MITOCHONDRIAL DYSFUNCTION IN THE DEVELOPMENT AND PROGRESSION OF NUMEROUS CHRONIC DISEASES, WHICH MAY BE PARTIALLY DUE TO MODIFICATIONS IN MITOCHONDRIAL DNA (MTDNA). THERE IS ALSO MOUNTING EVIDENCE THAT EPIGENETIC MODIFICATIONS TO MTDNA MAY BE AN ADDITIONAL LAYER OF REGULATION THAT CONTROLS MITOCHONDRIAL BIOGENESIS AND FUNCTION. SEVERAL ENVIRONMENTAL FACTORS (EG, SMOKING, AIR POLLUTION) HAVE BEEN ASSOCIATED WITH ALTERED MTDNA METHYLATION IN A HANDFUL OF MECHANISTIC STUDIES AND IN OBSERVATIONAL HUMAN STUDIES. HOWEVER, LITTLE IS UNDERSTOOD ABOUT OTHER ENVIRONMENTAL CONTAMINANTS THAT INDUCE MTDNA EPIGENETIC CHANGES. NUMEROUS ENVIRONMENTAL TOXICANTS ARE CLASSIFIED AS ENDOCRINE DISRUPTING CHEMICALS (EDCS). BEYOND THEIR ACTIONS ON HORMONAL PATHWAYS, EDC EXPOSURE IS ASSOCIATED WITH ELEVATED OXIDATIVE STRESS, WHICH MAY OCCUR THROUGH OR RESULT IN MITOCHONDRIAL DYSFUNCTION. ALTHOUGH ONLY A FEW STUDIES HAVE ASSESSED THE IMPACTS OF EDCS ON MTDNA METHYLATION, THE CURRENT REVIEW PROVIDES REASONS TO CONSIDER MTDNA EPIGENETIC DISRUPTION AS A MECHANISM OF ACTION OF EDCS AND REVIEWS POTENTIAL LIMITATIONS RELATED TO CURRENTLY AVAILABLE EVIDENCE. FIRST, THERE IS SUFFICIENT EVIDENCE THAT EDCS (INCLUDING BISPHENOLS AND PHTHALATES) DIRECTLY TARGET MITOCHONDRIAL FUNCTION, AND MORE DIRECT EVIDENCE IS NEEDED TO CONNECT THIS TO MTDNA METHYLATION. SECOND, THESE AND OTHER EDCS ARE POTENT MODULATORS OF NUCLEAR DNA EPIGENETICS, INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS. FINALLY, EDCS HAVE BEEN SHOWN TO DISRUPT SEVERAL MODULATORS OF MTDNA METHYLATION, INCLUDING DNA METHYLTRANSFERASES AND THE MITOCHONDRIAL TRANSCRIPTION FACTOR A/NUCLEAR RESPIRATORY FACTOR 1 PATHWAY. TAKEN TOGETHER, THESE STUDIES HIGHLIGHT THE NEED FOR FUTURE RESEARCH EVALUATING MTDNA EPIGENETIC DISRUPTION BY EDCS AND TO DETAIL SPECIFIC MECHANISMS RESPONSIBLE FOR SUCH DISRUPTIONS. 2020 10 6387 29 THE ROLE OF REACTIVE OXYGEN SPECIES IN ARSENIC TOXICITY. ARSENIC POISONING IS A GLOBAL HEALTH PROBLEM. CHRONIC EXPOSURE TO ARSENIC HAS BEEN ASSOCIATED WITH THE DEVELOPMENT OF A WIDE RANGE OF DISEASES AND HEALTH PROBLEMS IN HUMANS. ARSENIC EXPOSURE INDUCES THE GENERATION OF INTRACELLULAR REACTIVE OXYGEN SPECIES (ROS), WHICH MEDIATE MULTIPLE CHANGES TO CELL BEHAVIOR BY ALTERING SIGNALING PATHWAYS AND EPIGENETIC MODIFICATIONS, OR CAUSE DIRECT OXIDATIVE DAMAGE TO MOLECULES. ANTIOXIDANTS WITH THE POTENTIAL TO REDUCE ROS LEVELS HAVE BEEN SHOWN TO AMELIORATE ARSENIC-INDUCED LESIONS. HOWEVER, EMERGING EVIDENCE SUGGESTS THAT CONSTRUCTIVE ACTIVATION OF ANTIOXIDATIVE PATHWAYS AND DECREASED ROS LEVELS CONTRIBUTE TO CHRONIC ARSENIC TOXICITY IN SOME CASES. THIS REVIEW DETAILS THE PATHWAYS INVOLVED IN ARSENIC-INDUCED REDOX IMBALANCE, AS WELL AS CURRENT STUDIES ON PROPHYLAXIS AND TREATMENT STRATEGIES USING ANTIOXIDANTS. 2020 11 2144 29 EPIGENETIC LANDSCAPE OF STRESS SURFEIT DISORDERS: KEY ROLE FOR DNA METHYLATION DYNAMICS. CHRONIC EXPOSURE TO STRESS THROUGHOUT LIFESPAN ALTERS BRAIN STRUCTURE AND FUNCTION, INDUCING A MALADAPTIVE RESPONSE TO ENVIRONMENTAL STIMULI, THAT CAN CONTRIBUTE TO THE DEVELOPMENT OF A PATHOLOGICAL PHENOTYPE. STUDIES HAVE SHOWN THAT HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS DYSFUNCTION IS ASSOCIATED WITH VARIOUS NEUROPSYCHIATRIC DISORDERS, INCLUDING MAJOR DEPRESSIVE, ALCOHOL USE AND POST-TRAUMATIC STRESS DISORDERS. DOWNSTREAM ACTORS OF THE HPA AXIS, GLUCOCORTICOIDS ARE CRITICAL MEDIATORS OF THE STRESS RESPONSE AND EXERT THEIR FUNCTION THROUGH SPECIFIC RECEPTORS, I.E., THE GLUCOCORTICOID RECEPTOR (GR), HIGHLY EXPRESSED IN STRESS/REWARD-INTEGRATIVE PATHWAYS. GRS ARE LIGAND-ACTIVATED TRANSCRIPTION FACTORS THAT RECRUIT EPIGENETIC ACTORS TO REGULATE GENE EXPRESSION VIA DNA METHYLATION, ALTERING CHROMATIN STRUCTURE AND THUS SHAPING THE RESPONSE TO STRESS. THE DYNAMIC INTERPLAY BETWEEN STRESS RESPONSE AND EPIGENETIC MODIFIERS SUGGEST DNA METHYLATION PLAYS A KEY ROLE IN THE DEVELOPMENT OF STRESS SURFEIT DISORDERS. 2021 12 2513 26 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 13 1811 36 EFFECTS OF ARSENIC TOXICITY BEYOND EPIGENETIC MODIFICATIONS. WORLDWIDE CHRONIC ARSENIC (AS) POISONING BY ARSENIC-CONTAMINATED GROUNDWATER IS ONE OF THE MOST THREATENING PUBLIC HEALTH PROBLEMS. CHRONIC INORGANIC AS (INAS) EXPOSURE HAS BEEN ASSOCIATED WITH VARIOUS FORMS OF CANCERS AND NUMEROUS OTHER PATHOLOGICAL EFFECTS IN HUMANS, COLLECTIVELY KNOWN AS ARSENICOSIS. OVER THE PAST DECADE, EVIDENCE INDICATED THAT AS-INDUCED EPIGENETIC MODIFICATIONS HAVE A ROLE IN THE ADVERSE EFFECTS ON HUMAN HEALTH. THE MAIN OBJECTIVE OF THIS ARTICLE IS TO REVIEW THE EVIDENCE ON EPIGENETIC MODIFICATIONS INDUCED BY ARSENICALS. THE EPIGENETIC COMPONENTS PLAY A CRUCIAL ROLE IN THE REGULATION OF GENE EXPRESSION, AT BOTH TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL LEVELS. WE SYNTHESIZED THE LARGE BODY OF EXISTING RESEARCH ON ARSENIC EXPOSURE AND EPIGENETIC MECHANISMS OF HEALTH OUTCOMES WITH AN EMPHASIS ON RECENT PUBLICATIONS. CHANGES IN PATTERNS OF DNA METHYLATION, HISTONE POSTTRANSLATIONAL MODIFICATIONS, AND MICRORNAS HAVE BEEN REPEATEDLY OBSERVED AFTER INAS EXPOSURE IN LABORATORY STUDIES AND IN STUDIES OF HUMAN POPULATIONS. SUCH ALTERATIONS HAVE THE POTENTIAL TO DISTURB CELLULAR HOMEOSTASIS, RESULTING IN THE MODULATION OF KEY PATHWAYS IN THE AS-INDUCED CARCINOGENESIS. THE PRESENT ARTICLE REVIEWS RECENT DATA ON AS-INDUCED EPIGENETIC EFFECTS AND CONCLUDES THAT IT IS TIME FOR HEIGHTENED AWARENESS OF PATHOGENIC ARSENIC EXPOSURE, PARTICULARLY FOR PREGNANT WOMEN AND CHILDREN, GIVEN THE POTENTIAL FOR A LONG-LASTING DISTURBED CELLULAR HOMEOSTASIS. 2018 14 4683 40 NEW PERSPECTIVES ON FOLATE TRANSPORT IN RELATION TO ALCOHOLISM-INDUCED FOLATE MALABSORPTION--ASSOCIATION WITH EPIGENOME STABILITY AND CANCER DEVELOPMENT. FOLATES ARE MEMBERS OF THE B-CLASS OF VITAMINS, WHICH ARE REQUIRED FOR THE SYNTHESIS OF PURINES AND PYRIMIDINES, AND FOR THE METHYLATION OF ESSENTIAL BIOLOGICAL SUBSTANCES, INCLUDING PHOSPHOLIPIDS, DNA, AND NEUROTRANSMITTERS. FOLATES CANNOT BE SYNTHESIZED DE NOVO BY MAMMALS; HENCE, AN EFFICIENT INTESTINAL ABSORPTION PROCESS IS REQUIRED. INTESTINAL FOLATE TRANSPORT IS CARRIER-MEDIATED, PH-DEPENDENT AND ELECTRONEUTRAL, WITH SIMILAR AFFINITY FOR OXIDIZED AND REDUCED FOLIC ACID DERIVATIVES. THE VARIOUS TRANSPORTERS, I.E. REDUCED FOLATE CARRIER, PROTON-COUPLED FOLATE TRANSPORTER, FOLATE-BINDING PROTEIN, AND ORGANIC ANION TRANSPORTERS, ARE INVOLVED IN THE FOLATE TRANSPORT PROCESS IN VARIOUS TISSUES. ANY IMPAIRMENT IN UPTAKE OF FOLATE CAN LEAD TO A STATE OF FOLATE DEFICIENCY, THE MOST PREVALENT VITAMIN DEFICIENCY IN WORLD, AFFECTING 10% OF THE POPULATION IN THE USA. SUCH IMPAIRMENTS IN FOLATE TRANSPORT OCCUR IN A VARIETY OF CONDITIONS, INCLUDING CHRONIC USE OF ETHANOL, SOME INBORN HEREDITARY DISORDERS, AND CERTAIN DISEASES. AMONG THESE, ETHANOL INGESTION HAS BEEN THE MAJOR CONTRIBUTOR TO FOLATE DEFICIENCY. ETHANOL-ASSOCIATED FOLATE DEFICIENCY CAN DEVELOP BECAUSE OF DIETARY INADEQUACY, INTESTINAL MALABSORPTION, ALTERED HEPATOBILIARY METABOLISM, ENHANCED COLONIC METABOLISM, AND INCREASED RENAL EXCRETION. ETHANOL REDUCES THE INTESTINAL AND RENAL UPTAKE OF FOLATE BY ALTERING THE BINDING AND TRANSPORT KINETICS OF FOLATE TRANSPORT SYSTEMS. ALSO, ETHANOL REDUCES THE EXPRESSION OF FOLATE TRANSPORTERS IN BOTH INTESTINE AND KIDNEY, AND THIS MIGHT BE A CONTRIBUTING FACTOR FOR FOLATE MALABSORPTION, LEADING TO FOLATE DEFICIENCY. THE MAINTENANCE OF INTRACELLULAR FOLATE HOMEOSTASIS IS ESSENTIAL FOR THE ONE-CARBON TRANSFER REACTIONS NECESSARY FOR DNA SYNTHESIS AND BIOLOGICAL METHYLATION REACTIONS. DNA METHYLATION IS AN IMPORTANT EPIGENETIC DETERMINANT IN GENE EXPRESSION, IN THE MAINTENANCE OF DNA INTEGRITY AND STABILITY, IN CHROMOSOMAL MODIFICATIONS, AND IN THE DEVELOPMENT OF MUTATIONS. ETHANOL, A TOXIN THAT IS CONSUMED REGULARLY, HAS BEEN FOUND TO AFFECT THE METHYLATION OF DNA. IN ADDITION TO ITS EFFECT ON DNA METHYLATION DUE TO FOLATE DEFICIENCY, ETHANOL COULD DIRECTLY EXERT ITS EFFECT THROUGH ITS INTERACTION WITH ONE-CARBON METABOLISM, IMPAIRMENT OF METHYL GROUP SYNTHESIS, AND AFFECTING THE ENZYMES REGULATING THE SYNTHESIS OF S-ADENOSYLMETHIONINE, THE PRIMARY METHYL GROUP DONOR FOR MOST BIOLOGICAL METHYLATION REACTIONS. THUS, ETHANOL PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF SEVERAL DISEASES THROUGH ITS POTENTIAL ABILITY TO MODULATE THE METHYLATION OF BIOLOGICAL MOLECULES. THIS REVIEW DISCUSSES THE UNDERLYING MECHANISM OF FOLATE MALABSORPTION IN ALCOHOLISM, THE MECHANISM OF METHYLATION-ASSOCIATED SILENCING OF GENES, AND HOW THE INTERACTION BETWEEN ETHANOL AND FOLATE DEFICIENCY AFFECTS THE METHYLATION OF GENES, THEREBY MODULATING EPIGENOME STABILITY AND THE RISK OF CANCER. 2009 15 474 25 ARSENIC BIOTRANSFORMATION AS A CANCER PROMOTING FACTOR BY INDUCING DNA DAMAGE AND DISRUPTION OF REPAIR MECHANISMS. CHRONIC EXPOSURE TO ARSENIC IN DRINKING WATER POSES A MAJOR GLOBAL HEALTH CONCERN. POPULATIONS EXPOSED TO HIGH CONCENTRATIONS OF ARSENIC-CONTAMINATED DRINKING WATER SUFFER SERIOUS HEALTH CONSEQUENCES, INCLUDING ALARMING CANCER INCIDENCE AND DEATH RATES. ARSENIC IS BIOTRANSFORMED THROUGH SEQUENTIAL ADDITION OF METHYL GROUPS, ACQUIRED FROM S-ADENOSYLMETHIONINE (SAM). METABOLISM OF ARSENIC GENERATES A VARIETY OF GENOTOXIC AND CYTOTOXIC SPECIES, DAMAGING DNA DIRECTLY AND INDIRECTLY, THROUGH THE GENERATION OF REACTIVE OXIDATIVE SPECIES AND INDUCTION OF DNA ADDUCTS, STRAND BREAKS AND CROSS LINKS, AND INHIBITION OF THE DNA REPAIR PROCESS ITSELF. SINCE SAM IS THE METHYL GROUP DONOR USED BY DNA METHYLTRANSFERASES TO MAINTAIN NORMAL EPIGENETIC PATTERNS IN ALL HUMAN CELLS, ARSENIC IS ALSO POSTULATED TO AFFECT MAINTENANCE OF NORMAL DNA METHYLATION PATTERNS, CHROMATIN STRUCTURE, AND GENOMIC STABILITY. THE BIOLOGICAL PROCESSES UNDERLYING THE CANCER PROMOTING FACTORS OF ARSENIC METABOLISM, RELATED TO DNA DAMAGE AND REPAIR, WILL BE DISCUSSED HERE. 2011 16 6403 33 THE ROLES OF INDUCIBLE CHROMATIN AND TRANSCRIPTIONAL MEMORY IN CELLULAR DEFENSE SYSTEM RESPONSES TO REDOX-ACTIVE POLLUTANTS. PEOPLE ARE EXPOSED TO WIDE RANGE OF REDOX-ACTIVE ENVIRONMENTAL POLLUTANTS. AIR POLLUTION, HEAVY METALS, PESTICIDES, AND ENDOCRINE DISRUPTING CHEMICALS CAN DISRUPT CELLULAR REDOX STATUS. REDOX-ACTIVE POLLUTANTS IN OUR ENVIRONMENT ALL TRIGGER THEIR OWN SETS OF SPECIFIC CELLULAR RESPONSES, BUT THEY ALSO ACTIVATE A COMMON SET OF GENERAL STRESS RESPONSES THAT BUFFER THE CELL AGAINST HOMEOSTATIC INSULTS. THESE CELLULAR DEFENSE SYSTEM (CDS) PATHWAYS INCLUDE THE HEAT SHOCK RESPONSE, THE OXIDATIVE STRESS RESPONSE, THE HYPOXIA RESPONSE, THE UNFOLDED PROTEIN RESPONSE, THE DNA DAMAGE RESPONSE, AND THE GENERAL STRESS RESPONSE MEDIATED BY THE STRESS-ACTIVATED P38 MITOGEN-ACTIVATED PROTEIN KINASE. OVER THE PAST TWO DECADES, THE FIELD OF ENVIRONMENTAL EPIGENETICS HAS INVESTIGATED EPIGENETIC RESPONSES TO ENVIRONMENTAL POLLUTANTS, INCLUDING REDOX-ACTIVE POLLUTANTS. STUDIES OF THESE RESPONSES HIGHLIGHT THE ROLE OF CHROMATIN MODIFICATIONS IN CONTROLLING THE TRANSCRIPTIONAL RESPONSE TO POLLUTANTS AND THE ROLE OF TRANSCRIPTIONAL MEMORY, OFTEN REFERRED TO AS "EPIGENETIC REPROGRAMMING", IN PREDISPOSING PREVIOUSLY EXPOSED INDIVIDUALS TO MORE POTENT TRANSCRIPTIONAL RESPONSES ON SECONDARY CHALLENGE. MY CENTRAL THESIS IN THIS REVIEW IS THAT HIGH DOSE OR CHRONIC EXPOSURE TO REDOX-ACTIVE POLLUTANTS LEADS TO TRANSCRIPTIONAL MEMORIES AT CDS TARGET GENES THAT INFLUENCE THE CELL'S ABILITY TO MOUNT PROTECTIVE RESPONSES. TO SUPPORT THIS THESIS, I WILL: (1) SUMMARIZE THE KNOWN CHROMATIN FEATURES REQUIRED FOR INDUCIBLE GENE ACTIVATION; (2) REVIEW THE KNOWN FORMS OF TRANSCRIPTIONAL MEMORY; (3) DISCUSS THE ROLES OF INDUCIBLE CHROMATIN AND TRANSCRIPTIONAL MEMORY IN CDS RESPONSES THAT ARE ACTIVATED BY REDOX-ACTIVE ENVIRONMENTAL POLLUTANTS; AND (4) PROPOSE A CONCEPTUAL FRAMEWORK FOR CDS PATHWAY RESPONSIVENESS AS A READOUT OF TOTAL CELLULAR EXPOSURE TO REDOX-ACTIVE POLLUTANTS. 2021 17 1532 20 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 18 2833 23 FOLATE AND DNA METHYLATION: A REVIEW OF MOLECULAR MECHANISMS AND THE EVIDENCE FOR FOLATE'S ROLE. DNA METHYLATION IS AN EPIGENETIC MODIFICATION CRITICAL TO NORMAL GENOME REGULATION AND DEVELOPMENT. THE VITAMIN FOLATE IS A KEY SOURCE OF THE ONE CARBON GROUP USED TO METHYLATE DNA. BECAUSE NORMAL MAMMALIAN DEVELOPMENT IS DEPENDENT ON DNA METHYLATION, THERE IS ENORMOUS INTEREST IN ASSESSING THE POTENTIAL FOR CHANGES IN FOLATE INTAKE TO MODULATE DNA METHYLATION BOTH AS A BIOMARKER FOR FOLATE STATUS AND AS A MECHANISTIC LINK TO DEVELOPMENTAL DISORDERS AND CHRONIC DISEASES INCLUDING CANCER. THIS REVIEW HIGHLIGHTS THE ROLE OF DNA METHYLATION IN NORMAL GENOME FUNCTION, HOW IT CAN BE ALTERED, AND THE EVIDENCE OF THE ROLE OF FOLATE/FOLIC ACID IN THESE PROCESSES. 2012 19 2399 34 EPIGENETIC REPROGRAMMING OF HOST GENES IN VIRAL AND MICROBIAL PATHOGENESIS. ONE OF THE KEY QUESTIONS IN THE STUDY OF MAMMALIAN GENE REGULATION IS HOW EPIGENETIC METHYLATION PATTERNS ON HISTONES AND DNA ARE INITIATED AND ESTABLISHED. THESE STABLE, HERITABLE, COVALENT MODIFICATIONS ARE LARGELY ASSOCIATED WITH THE REPRESSION OR SILENCING OF GENE TRANSCRIPTION, AND WHEN DEREGULATED CAN BE INVOLVED IN THE DEVELOPMENT OF HUMAN DISEASES SUCH AS CANCER. THIS ARTICLE REVIEWS EXAMPLES OF VIRUSES AND BACTERIA KNOWN OR THOUGHT TO INDUCE EPIGENETIC CHANGES IN HOST CELLS, AND HOW THIS MIGHT CONTRIBUTE TO DISEASE. THE HERITABLE NATURE OF THESE PROCESSES IN GENE REGULATION SUGGESTS THAT THEY COULD PLAY IMPORTANT ROLES IN CHRONIC DISEASES ASSOCIATED WITH MICROBIAL PERSISTENCE; THEY MIGHT ALSO EXPLAIN SO-CALLED 'HIT-AND-RUN' PHENOMENA IN INFECTIOUS DISEASE PATHOGENESIS. 2010 20 4327 25 MICRORNAS MODULATE INTERACTIONS BETWEEN STRESS AND RISK FOR COCAINE ADDICTION. EXPOSURE TO STRESS INCREASES VULNERABILITY TO DRUG ABUSE, AS WELL AS RELAPSE LIABILITY IN ADDICTED INDIVIDUALS. CHRONIC DRUG USE ALTERS STRESS RESPONSE IN A MANNER THAT INCREASES DRUG SEEKING BEHAVIORS AND RELAPSE. DRUG EXPOSURE AND WITHDRAWAL HAVE BEEN SHOWN TO ALTER STRESS RESPONSES, AND CORTICOSTEROID MEDIATORS OF STRESS HAVE BEEN SHOWN TO IMPACT ADDICTION-RELATED BRAIN FUNCTION AND DRUG-SEEKING BEHAVIOR. DESPITE THE DOCUMENTED INTERPLAY BETWEEN STRESS AND SUBSTANCE ABUSE, THE MECHANISMS BY WHICH STRESS EXPOSURE AND DRUG SEEKING INTERACT REMAIN LARGELY UNKNOWN. RECENT STUDIES INDICATE THAT MICRORNAS (MIRNA) PLAY A SIGNIFICANT ROLE IN STRESS MODULATION AS WELL AS ADDICTION-RELATED PROCESSES INCLUDING NEUROGENESIS, SYNAPSE DEVELOPMENT, PLASTICITY, DRUG ACQUISITION, WITHDRAWAL AND RELAPSE. MIRNAS ARE SHORT NON-CODING RNAS THAT FUNCTION AS BIDIRECTIONAL EPIGENETIC MODULATORS OF GENE EXPRESSION THROUGH IMPERFECT SEQUENCE TARGETED DEGRADATION AND/OR TRANSLATIONAL REPRESSION OF MRNAS. THEY SERVE AS DYNAMIC REGULATORS OF CNS PHYSIOLOGY AND PATHOPHYSIOLOGY, AND FACILITATE RAPID AND LONG-LASTING CHANGES TO COMPLEX SYSTEMS AND BEHAVIORS. MIRNAS FUNCTION IN GLUCOCORTICOID SIGNALING AND THE MESOLIMBIC DOPAMINE REWARD SYSTEM, AS WELL AS MOOD DISORDERS RELATED TO DRUG WITHDRAWAL. THE LITERATURE SUGGESTS MIRNAS PLAY A PIVOTAL ROLE IN THE INTERACTION BETWEEN EXPOSURES TO STRESS, ADDICTION-RELATED PROCESSES, AND NEGATIVE AFFECTIVE STATES RESULTING FROM EXTENDED DRUG WITHDRAWAL. THIS MANUSCRIPT REVIEWS RECENT EVIDENCE FOR THE ROLE OF MIRNAS IN THE MODULATION OF STRESS AND COCAINE RESPONSES, AND DISCUSSES POTENTIAL MEDIATION OF THE INTERACTION OF THESE SYSTEMS BY MIRNAS. UNCOVERING THE MECHANISM BEHIND THE ASSOCIATION OF STRESS AND DRUG TAKING HAS THE POTENTIAL TO IMPACT THE TREATMENT OF DRUG ABUSE AND PREVENTION OF RELAPSE. FURTHER COMPREHENSION OF THESE COMPLEX INTERACTIONS MAY PROVIDE PROMISING NEW TARGETS FOR THE TREATMENT OF DRUG ADDICTION. 2016