1 2567 124 EPIGENETICS MODIFIERS: POTENTIAL HUB FOR UNDERSTANDING AND TREATING NEURODEVELOPMENTAL DISORDERS FROM HYPOXIC INJURY. BACKGROUND: THE FETAL BRAIN IS ADAPTED TO THE HYPOXIC CONDITIONS PRESENT DURING NORMAL IN UTERO DEVELOPMENT. RELATIVELY MORE HYPOXIC STATES, EITHER CHRONIC OR ACUTE, ARE PATHOLOGIC AND CAN LEAD TO SIGNIFICANT LONG-TERM NEURODEVELOPMENTAL SEQUELAE. IN UTERO HYPOXIC INJURY IS ASSOCIATED WITH NEONATAL MORTALITY AND MILLIONS OF LIVES LIVED WITH VARYING DEGREES OF DISABILITY. MAIN BODY: GENETIC STUDIES OF CHILDREN WITH NEURODEVELOPMENTAL DISEASE INDICATE THAT EPIGENETIC MODIFIERS REGULATING DNA METHYLATION AND HISTONE REMODELING ARE CRITICAL FOR NORMAL BRAIN DEVELOPMENT. EPIGENETIC MODIFIERS ARE ALSO REGULATED BY ENVIRONMENTAL STIMULI, SUCH AS HYPOXIA. INDEED, EPIGENETIC MODIFIERS THAT ARE MUTATED IN CHILDREN WITH GENETIC NEURODEVELOPMENTAL DISEASES ARE REGULATED BY HYPOXIA IN A NUMBER OF PRECLINICAL MODELS AND MAY BE PART OF THE MECHANISM FOR THE LONG-TERM NEURODEVELOPMENTAL SEQUELAE SEEM IN CHILDREN WITH HYPOXIC BRAIN INJURY. THUS, A COMPREHENSIVE UNDERSTANDING THE ROLE OF DNA METHYLATION AND HISTONE MODIFICATIONS IN HYPOXIC INJURY IS CRITICAL FOR DEVELOPING NOVEL STRATEGIES TO TREAT CHILDREN WITH HYPOXIC INJURY. CONCLUSIONS: THIS REVIEW FOCUSES ON OUR CURRENT UNDERSTANDING OF THE INTERSECTION BETWEEN EPIGENETICS, BRAIN DEVELOPMENT, AND HYPOXIA. OPPORTUNITIES FOR THE USE OF EPIGENETICS AS BIOMARKERS OF NEURODEVELOPMENTAL DISEASE AFTER HYPOXIC INJURY AND POTENTIAL CLINICAL EPIGENETICS TARGETS TO IMPROVE OUTCOMES AFTER INJURY ARE ALSO DISCUSSED. WHILE THERE HAVE BEEN MANY PUBLISHED STUDIES ON THE EPIGENETICS OF HYPOXIA, MORE ARE NEEDED IN THE DEVELOPING BRAIN IN ORDER TO DETERMINE WHICH EPIGENETIC PATHWAYS MAY BE MOST IMPORTANT FOR MITIGATING THE LONG-TERM CONSEQUENCES OF HYPOXIC BRAIN INJURY. 2020 2 2523 51 EPIGENETICS AND THE TRANSITION FROM ACUTE TO CHRONIC PAIN. OBJECTIVE: THE OBJECTIVE OF THIS STUDY WAS TO REVIEW THE EPIGENETIC MODIFICATIONS INVOLVED IN THE TRANSITION FROM ACUTE TO CHRONIC PAIN AND TO IDENTIFY POTENTIAL TARGETS FOR THE DEVELOPMENT OF NOVEL, INDIVIDUALIZED PAIN THERAPEUTICS. BACKGROUND: EPIGENETICS IS THE STUDY OF HERITABLE MODIFICATIONS IN GENE EXPRESSION AND PHENOTYPE THAT DO NOT REQUIRE A CHANGE IN GENETIC SEQUENCE TO MANIFEST THEIR EFFECTS. ENVIRONMENTAL TOXINS, MEDICATIONS, DIET, AND PSYCHOLOGICAL STRESSES CAN ALTER EPIGENETIC PROCESSES SUCH AS DNA METHYLATION, HISTONE ACETYLATION, AND RNA INTERFERENCE. AS EPIGENETIC MODIFICATIONS POTENTIALLY PLAY AN IMPORTANT ROLE IN INFLAMMATORY CYTOKINE METABOLISM, STEROID RESPONSIVENESS, AND OPIOID SENSITIVITY, THEY ARE LIKELY KEY FACTORS IN THE DEVELOPMENT OF CHRONIC PAIN. ALTHOUGH OUR KNOWLEDGE OF THE HUMAN GENETIC CODE AND DISEASE-ASSOCIATED POLYMORPHISMS HAS GROWN SIGNIFICANTLY IN THE PAST DECADE, WE HAVE NOT YET BEEN ABLE TO ELUCIDATE THE MECHANISMS THAT LEAD TO THE DEVELOPMENT OF PERSISTENT PAIN AFTER NERVE INJURY OR SURGERY. DESIGN: THIS IS A FOCUSED LITERATURE REVIEW OF EPIGENETIC SCIENCE AND ITS RELATIONSHIP TO CHRONIC PAIN. RESULTS: SIGNIFICANT LABORATORY AND CLINICAL DATA SUPPORT THE NOTION THAT EPIGENETIC MODIFICATIONS ARE AFFECTED BY THE ENVIRONMENT AND LEAD TO DIFFERENTIAL GENE EXPRESSION. SIMILAR TO MECHANISMS INVOLVED IN THE DEVELOPMENT OF CANCER, NEURODEGENERATIVE DISEASE, AND INFLAMMATORY DISORDERS, THE LITERATURE ENDORSES AN IMPORTANT POTENTIAL ROLE FOR EPIGENETICS IN CHRONIC PAIN. CONCLUSIONS: EPIGENETIC ANALYSIS MAY IDENTIFY MECHANISMS CRITICAL TO THE DEVELOPMENT OF CHRONIC PAIN AFTER INJURY, AND MAY PROVIDE NEW PATHWAYS AND TARGET MECHANISMS FOR FUTURE DRUG DEVELOPMENT AND INDIVIDUALIZED MEDICINE. 2012 3 3404 42 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 4 5164 43 PRECLINICAL AND CLINICAL EVIDENCE OF DNA METHYLATION CHANGES IN RESPONSE TO TRAUMA AND CHRONIC STRESS. EXPOSURE TO CHRONIC STRESS, EITHER REPEATED SEVERE ACUTE OR MODERATE SUSTAINED STRESS, IS ONE OF THE STRONGEST RISK FACTORS FOR THE DEVELOPMENT OF PSYCHOPATHOLOGIES SUCH AS POST-TRAUMATIC STRESS DISORDER AND DEPRESSION. CHRONIC STRESS IS LINKED WITH SEVERAL LASTING BIOLOGICAL CONSEQUENCES, PARTICULARLY TO THE STRESS ENDOCRINE SYSTEM BUT ALSO AFFECTING INTERMEDIATE PHENOTYPES SUCH AS BRAIN STRUCTURE AND FUNCTION, IMMUNE FUNCTION, AND BEHAVIOR. ALTHOUGH GENETIC PREDISPOSITION CONFERS A PROPORTION OF THE RISK, THE MOST RELEVANT MOLECULAR MECHANISMS DETERMINING THOSE SUSCEPTIBLE AND RESILIENT TO THE EFFECTS OF STRESS AND TRAUMA MAY BE EPIGENETIC. EPIGENETICS REFERS TO THE MECHANISMS THAT REGULATE GENOMIC INFORMATION BY DYNAMICALLY CHANGING THE PATTERNS OF TRANSCRIPTION AND TRANSLATION OF GENES. MOUNTING EVIDENCE FROM PRECLINICAL RODENT AND CLINICAL POPULATION STUDIES STRONGLY SUPPORT THAT EPIGENETIC MODIFICATIONS CAN OCCUR IN RESPONSE TO TRAUMATIC AND CHRONIC STRESS. HERE, WE DISCUSS THIS LITERATURE EXAMINING STRESS-INDUCED EPIGENETIC CHANGES IN PRECLINICAL MODELS AND CLINICAL COHORTS OF STRESS AND TRAUMA OCCURRING EARLY IN LIFE OR IN ADULTHOOD. WE HIGHLIGHT THAT A COMPLEX RELATIONSHIP BETWEEN THE TIMING OF ENVIRONMENTAL STRESSORS AND GENETIC PREDISPOSITIONS LIKELY MEDIATE THE RESPONSE TO CHRONIC STRESS OVER TIME, AND THAT A BETTER UNDERSTANDING OF EPIGENETIC CHANGES IS NEEDED BY FURTHER INVESTIGATIONS IN LONGITUDINAL AND POSTMORTEM BRAIN CLINICAL COHORTS. 2017 5 2154 41 EPIGENETIC MECHANISMS AND KIDNEY DISEASES. IN RECENT YEARS, MOLECULAR RESEARCH HAS BROUGHT TO LIGHT A SERIES OF MECHANISMS INVOLVED IN THE REGULATION OF GENE FUNCTION WITHOUT ALTERING THE DNA SEQUENCE. THESE MECHANISMS ARE DESCRIBED WITH THE TERM "EPIGENETICS" AND INCLUDE MODIFICATIONS IN THE STRUCTURE OF THE HUMAN GENOME, LEADING TO HERITABLE AND POTENTIALLY REVERSIBLE CHANGES IN GENE EXPRESSION. THERE IS NOW INCREASING EVIDENCE SUGGESTING THAT SEVERAL CHARACTERISTIC FEATURES OF CHRONIC KIDNEY DISEASE SUCH AS HYPERHOMOCYSTEINEMIA, SUBCLINICAL INFLAMMATION, INCREASED OXIDATIVE STRESS AND OTHERS MAY AFFECT THE HUMAN EPIGENOME. IN ADDITION, ANIMAL STUDIES HAVE SUGGESTED A POSSIBLE LINK BETWEEN NUTRITION AND ENVIRONMENTAL EXPOSURE DURING THE PERICONCEPTIONAL PERIOD AND EPIGENETIC CHANGES IN THE EXPRESSION OF MAJOR GENES IMPLICATED IN KIDNEY ORGANOGENESIS; THESE CHANGES RESULT IN A DIMINISHED NUMBER OF NEPHRONS IN THE DEVELOPING KIDNEY, WHICH PREDISPOSES TO AN INCREASED RISK FOR HYPERTENSION AND CHRONIC KIDNEY DISEASE IN FUTURE LIFE. THE UNDERSTANDING OF THE ROLE OF EPIGENETIC PHENOMENA IN THE PATHOGENESIS OF CHRONIC KIDNEY DISEASE OPENS NEW AVENUES FOR FUTURE THERAPEUTIC STRATEGIES, THROUGH THE DEVELOPMENT OF PHARMACEUTICAL AGENTS THAT TARGET DIRECTLY WITH THE CHANGES IN THE HUMAN EPIGENOME. SUCH EPIGENETIC DRUGS ARE ALREADY IN CLINICAL USE FOR THE TREATMENT OF CANCER AS WELL AS UNDER INVESTIGATION FOR THE USE IN OTHER DISEASES. THIS REVIEW WILL SUMMARIZE THE EXISTING DATA ON THE LINK BETWEEN EPIGENETIC MECHANISMS AND CHRONIC UREMIC MILIEU, AS WELL AS THE PROMISING RESULTS OF ONGOING RESEARCH IN THE FIELD OF EPIGENETIC DRUGS THAT COULD REPRESENT ADDITIONAL OPTIONS IN OUR THERAPEUTIC ARMAMENTARIUM FOR PATIENTS WITH CHRONIC KIDNEY DISEASE. 2011 6 5376 46 RECENT DEVELOPMENTS IN EPIGENETICS OF ACUTE AND CHRONIC KIDNEY DISEASES. THE GROWING EPIDEMIC OF OBESITY AND DIABETES, THE AGING POPULATION AS WELL AS PREVALENCE OF DRUG ABUSE HAS LED TO SIGNIFICANT INCREASES IN THE RATES OF THE CLOSELY ASSOCIATED ACUTE AND CHRONIC KIDNEY DISEASES, INCLUDING DIABETIC NEPHROPATHY. FURTHERMORE, EVIDENCE SHOWS THAT PARENTAL BEHAVIOR AND DIET CAN AFFECT THE PHENOTYPE OF SUBSEQUENT GENERATIONS VIA EPIGENETIC TRANSMISSION MECHANISMS. THESE DATA SUGGEST A STRONG INFLUENCE OF THE ENVIRONMENT ON DISEASE SUSCEPTIBILITY AND THAT, APART FROM GENETIC SUSCEPTIBILITY, EPIGENETIC MECHANISMS NEED TO BE EVALUATED TO GAIN CRITICAL NEW INFORMATION ABOUT KIDNEY DISEASES. EPIGENETICS IS THE STUDY OF PROCESSES THAT CONTROL GENE EXPRESSION AND PHENOTYPE WITHOUT ALTERATIONS IN THE UNDERLYING DNA SEQUENCE. EPIGENETIC MODIFICATIONS, INCLUDING CYTOSINE DNA METHYLATION AND COVALENT POST-TRANSLATIONAL MODIFICATIONS OF HISTONES IN CHROMATIN, ARE PART OF THE EPIGENOME, THE INTERFACE BETWEEN THE STABLE GENOME AND THE VARIABLE ENVIRONMENT. THIS DYNAMIC EPIGENETIC LAYER RESPONDS TO EXTERNAL ENVIRONMENTAL CUES TO INFLUENCE THE EXPRESSION OF GENES ASSOCIATED WITH DISEASE STATES. THE FIELD OF EPIGENETICS HAS SEEN REMARKABLE GROWTH IN THE PAST FEW YEARS WITH SIGNIFICANT ADVANCES IN BASIC BIOLOGY, CONTRIBUTIONS TO HUMAN DISEASE, AS WELL AS EPIGENOMICS TECHNOLOGIES. FURTHER UNDERSTANDING OF HOW THE RENAL CELL EPIGENOME IS ALTERED BY METABOLIC AND OTHER STIMULI CAN YIELD NOVEL NEW INSIGHTS INTO THE PATHOGENESIS OF KIDNEY DISEASES. IN THIS REVIEW, WE HAVE DISCUSSED THE CURRENT KNOWLEDGE ON THE ROLE OF EPIGENETIC MECHANISMS (PRIMARILY DNAME AND HISTONE MODIFICATIONS) IN ACUTE AND CHRONIC KIDNEY DISEASES, AND THEIR TRANSLATIONAL POTENTIAL TO IDENTIFY MUCH NEEDED NEW THERAPIES. 2015 7 3848 35 IS EPIGENETICS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE? BACKGROUND: EPIGENETIC MECHANISMS PROVIDE ONE POTENTIAL EXPLANATION FOR HOW ENVIRONMENTAL INFLUENCES IN EARLY LIFE CAUSE LONG-TERM CHANGES IN CHRONIC DISEASE SUSCEPTIBILITY. WHEREAS EPIGENETIC DYSREGULATION IS INCREASINGLY IMPLICATED IN VARIOUS RARE DEVELOPMENTAL SYNDROMES AND CANCER, THE ROLE OF EPIGENETICS IN COMPLEX CHRONIC DISEASES, SUCH AS CARDIOVASCULAR DISEASE, TYPE 2 DIABETES AND OBESITY, REMAINS LARGELY UNCHARACTERIZED. EXTENSIVE WORK IN ANIMAL MODELS IS REQUIRED TO DEVELOP SPECIFIC HYPOTHESES THAT CAN BE PRACTICABLY TESTED IN HUMANS. ANIMAL MODELS: WE HAVE DEVELOPED A MOUSE MODEL SHOWING THAT METHYL DONOR SUPPLEMENTATION PREVENTS TRANSGENERATIONAL AMPLIFICATION OF OBESITY, SUGGESTING A ROLE FOR DNA METHYLATION IN THE DEVELOPMENTAL ESTABLISHMENT OF BODY WEIGHT REGULATION. CONCLUSIONS: COUPLING SUCH MODELS WITH RECENTLY DEVELOPED EPIGENOMIC TECHNOLOGIES SHOULD ULTIMATELY ENABLE US TO DETERMINE IF EPIGENETICS IS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE. 2009 8 2346 33 EPIGENETIC REGULATION OF METABOLISM AND INFLAMMATION BY CALORIE RESTRICTION. CHRONIC CALORIC RESTRICTION (CR) WITHOUT MALNUTRITION IS KNOWN TO AFFECT DIFFERENT CELLULAR PROCESSES SUCH AS STEM CELL FUNCTION, CELL SENESCENCE, INFLAMMATION, AND METABOLISM. DESPITE THE DIFFERENCES IN THE IMPLEMENTATION OF CR, THE REDUCTION OF CALORIES PRODUCES A WIDESPREAD BENEFICIAL EFFECT IN NONCOMMUNICABLE CHRONIC DISEASES, WHICH CAN BE EXPLAINED BY IMPROVEMENTS IN IMMUNO-METABOLIC ADAPTATION. CELLULAR ADAPTATION THAT OCCURS IN RESPONSE TO DIETARY PATTERNS CAN BE EXPLAINED BY ALTERATIONS IN EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNA. IN THIS REVIEW, WE DEFINE THESE MODIFICATIONS AND SYSTEMATICALLY SUMMARIZE THE CURRENT EVIDENCE RELATED TO CR AND THE EPIGENOME. WE THEN EXPLAIN THE SIGNIFICANCE OF GENOME-WIDE EPIGENETIC MODIFICATIONS IN THE CONTEXT OF DISEASE DEVELOPMENT. ALTHOUGH SUBSTANTIAL EVIDENCE EXISTS FOR THE WIDESPREAD EFFECT OF CR ON LONGEVITY, THERE IS NO CONSENSUS REGARDING THE EPIGENETIC REGULATIONS OF THE UNDERLYING CELLULAR MECHANISMS THAT LEAD TO IMPROVED HEALTH. WE PROVIDE COMPELLING EVIDENCE THAT CR PRODUCES LONG-LASTING EPIGENETIC EFFECTS THAT MEDIATE EXPRESSION OF GENES RELATED TO IMMUNO-METABOLIC PROCESSES. EPIGENETIC REPROGRAMMING OF THE UNDERLYING CHRONIC LOW-GRADE INFLAMMATION BY CR CAN LEAD TO IMMUNO-METABOLIC ADAPTATIONS THAT ENHANCE QUALITY OF LIFE, EXTEND LIFESPAN, AND DELAY CHRONIC DISEASE ONSET. 2019 9 4125 32 MECHANISMS OF DISEASE: IN UTERO PROGRAMMING IN THE PATHOGENESIS OF HYPERTENSION. NUTRITIONAL AND OTHER ENVIRONMENTAL CUES DURING DEVELOPMENT CAN PERMANENTLY ALTER THE STRUCTURE, HOMEOSTATIC SYSTEMS, AND FUNCTIONS OF THE BODY. THIS PHENOMENON HAS BEEN REFERRED TO AS 'PROGRAMMING'. EPIDEMIOLOGICAL AND ANIMAL STUDIES SHOW THAT PROGRAMMED EFFECTS OPERATE WITHIN THE NORMAL RANGE OF GROWTH AND DEVELOPMENT, AND INFLUENCE THE RISK OF CHRONIC DISEASE IN ADULT LIFE. WE REVIEW THE EVIDENCE THAT THESE EFFECTS INCLUDE REDUCED NEPHRON NUMBER AND COMPENSATORY ADAPTATIONS, WHICH MIGHT LEAD TO HYPERTENSION, AND PERHAPS ACCELERATE THE DECLINE IN RENAL FUNCTION THAT ACCOMPANIES AGING. THESE PROCESSES MIGHT BE EXACERBATED BY PROGRAMMED CHANGES IN VASCULAR STRUCTURE AND FUNCTION, AND ALTERATIONS IN ENDOCRINE AND METABOLIC HOMEOSTASIS. PROGRAMMED EFFECTS MIGHT BE INITIATED AS EARLY AS THE PERICONCEPTUAL PHASE OF DEVELOPMENT, AND COULD INVOLVE EPIGENETIC CHANGES IN GENE EXPRESSION OR ALTERED STEM CELL ALLOCATION. BETTER UNDERSTANDING OF THESE PROCESSES COULD LEAD TO THE DEVELOPMENT OF NOVEL DIAGNOSTIC AND PREVENTIVE MEASURES, AND TO EARLY DETECTION OF AT-RISK INDIVIDUALS. BY MONITORING BLOOD PRESSURE, WEIGHT, AND RENAL FUNCTION IN CHILDREN, IT MIGHT BE POSSIBLE TO REDUCE THE RISK OF CARDIOVASCULAR AND RENAL DISEASE IN LATER LIFE. 2006 10 6866 41 [PAIN AND EMOTIONAL DYSREGULATION: CELLULAR MEMORY DUE TO PAIN]. GENETIC FACTORS ARE INVOLVED IN DETERMINANTS FOR THE RISK OF PSYCHIATRIC DISORDERS, AND NEUROLOGICAL AND NEURODEGENERATIVE DISEASES. CHRONIC PAIN STIMULI AND INTENSE PAIN HAVE EFFECTS AT A CELLULAR AND/OR GENE EXPRESSION LEVEL, AND WILL EVENTUALLY INDUCE "CELLULAR MEMORY DUE TO PAIN", WHICH MEANS THAT TISSUE DAMAGE, EVEN IF ONLY TRANSIENT, CAN ELICIT EPIGENETICALLY ABNORMAL TRANSCRIPTION/TRANSLATION AND POST-TRANSLATIONAL MODIFICATION IN RELATED CELLS DEPENDING ON THE DEGREE OR KIND OF INJURY OR ASSOCIATED CONDITIONS. SUCH CELL MEMORY/TRANSFORMATION DUE TO PAIN CAN CAUSE AN ABNORMALITY IN A FUNDAMENTAL INTRACELLULAR RESPONSE, SUCH AS A CHANGE IN THE THREE-DIMENSIONAL STRUCTURE OF DNA, TRANSCRIPTION, OR TRANSLATION. ON THE OTHER HAND, PAIN IS A MULTIDIMENSIONAL EXPERIENCE WITH SENSORY-DISCRIMINATIVE AND MOTIVATIONAL-AFFECTIVE COMPONENTS. RECENT HUMAN BRAIN IMAGING STUDIES HAVE EXAMINED DIFFERENCES IN ACTIVITY IN THE NUCLEUS ACCUMBENS BETWEEN CONTROLS AND PATIENTS WITH CHRONIC PAIN, AND HAVE REVEALED THAT THE NUCLEUS ACCUMBENS PLAYS A ROLE IN PREDICTING THE VALUE OF A NOXIOUS STIMULUS AND ITS OFFSET, AND IN THE CONSEQUENT CHANGES IN THE MOTIVATIONAL STATE. IN THIS REVIEW, WE PROVIDE A VERY BRIEF OVERVIEW OF A COMPREHENSIVE UNDERSTANDING OF CHRONIC PAIN ASSOCIATED WITH EMOTIONAL DYSREGULATION DUE TO TRANSCRIPTIONAL REGULATION, EPIGENETIC MODIFICATION AND MIRNA REGULATION. 2015 11 2963 23 GENETIC AND EPIGENETIC MECHANISMS LINKING PAIN AND PSYCHIATRIC DISORDERS. THE NEUROPHYSIOLOGICAL LINK BETWEEN NEUROPATHIC PAIN AND DEPRESSION REMAINS UNKNOWN DESPITE EVIDENT HIGH COMORBIDITY OF THESE TWO DISORDERS. HOWEVER, THERE IS CONVINCING EVIDENCE THAT GENOTYPE PLAYS A ROLE IN BOTH PAIN AND DEPRESSION. USING VARIOUS TYPES OF GENETIC ANALYSIS - POPULATION GENETICS, CYTOGENETICS AND MOLECULAR TECHNOLOGIES - SPECIFIC GENES HAVE BEEN IMPLICATED IN MEDIATING ALMOST ALL ASPECTS OF NOCICEPTION AND MOOD DISORDERS. THE CURRENT REVIEW ATTEMPTS TO IDENTIFY SPECIFIC GENES AND EPIGENETIC MECHANISMS COMMON TO BOTH DISORDERS. IT IS CONCLUDED THAT EXTERNAL AND INTERNAL FACTORS (INFLAMMATION, STRESS, GENDER, ETC.) THAT CONTRIBUTE TO THE PATHOLOGIES MAY DO SO THROUGH EPIGENETIC MECHANISMS THAT MAY AFFECT EXPRESSION OF THESE PARTICULAR GENES. THE POSSIBLE INVOLVEMENT OF EPIGENETIC REGULATION IN PAIN AND PSYCHIATRIC DISORDERS SUGGESTS THAT TREATMENTS TARGETING EPIGENETIC MECHANISMS THAT MEDIATE ADVERSE LIFE EVENTS SHOULD BE CONSIDERED. 2015 12 6133 48 THE EPIGENETIC ROLE OF VITAMIN C IN NEURODEVELOPMENT. THE MATERNAL DIET DURING PREGNANCY IS A KEY DETERMINANT OF OFFSPRING HEALTH. EARLY STUDIES HAVE LINKED POOR MATERNAL NUTRITION DURING GESTATION WITH A PROPENSITY FOR THE DEVELOPMENT OF CHRONIC CONDITIONS IN OFFSPRING. THESE CONDITIONS INCLUDE CARDIOVASCULAR DISEASE, TYPE 2 DIABETES AND EVEN COMPROMISED MENTAL HEALTH. WHILE MULTIPLE FACTORS MAY CONTRIBUTE TO THESE OUTCOMES, DISTURBED EPIGENETIC PROGRAMMING DURING EARLY DEVELOPMENT IS ONE POTENTIAL BIOLOGICAL MECHANISM. THE EPIGENOME IS PROGRAMMED PRIMARILY IN UTERO, AND DURING THIS TIME, THE DEVELOPING FETUS IS HIGHLY SUSCEPTIBLE TO ENVIRONMENTAL FACTORS SUCH AS NUTRITIONAL INSULTS. DURING NEURODEVELOPMENT, EPIGENETIC PROGRAMMING COORDINATES THE FORMATION OF PRIMITIVE CENTRAL NERVOUS SYSTEM STRUCTURES, NEUROGENESIS, AND NEUROPLASTICITY. DYSREGULATED EPIGENETIC PROGRAMMING HAS BEEN IMPLICATED IN THE AETIOLOGY OF SEVERAL NEURODEVELOPMENTAL DISORDERS SUCH AS TATTON-BROWN-RAHMAN SYNDROME. ACCORDINGLY, THERE IS GREAT INTEREST IN DETERMINING HOW MATERNAL NUTRIENT AVAILABILITY IN PREGNANCY MIGHT AFFECT THE EPIGENETIC STATUS OF OFFSPRING, AND HOW SUCH INFLUENCES MAY PRESENT PHENOTYPICALLY. IN RECENT YEARS, A NUMBER OF EPIGENETIC ENZYMES THAT ARE ACTIVE DURING EMBRYONIC DEVELOPMENT HAVE BEEN FOUND TO REQUIRE VITAMIN C AS A COFACTOR. THESE ENZYMES INCLUDE THE TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASES (TETS) AND THE JUMONJI C DOMAIN-CONTAINING HISTONE LYSINE DEMETHYLASES THAT CATALYSE THE OXIDATIVE REMOVAL OF METHYL GROUPS ON CYTOSINES AND HISTONE LYSINE RESIDUES, RESPECTIVELY. THESE ENZYMES ARE INTEGRAL TO EPIGENETIC REGULATION AND HAVE FUNDAMENTAL ROLES IN CELLULAR DIFFERENTIATION, THE MAINTENANCE OF PLURIPOTENCY AND DEVELOPMENT. THE DEPENDENCE OF THESE ENZYMES ON VITAMIN C FOR OPTIMAL CATALYTIC ACTIVITY ILLUSTRATES A POTENTIALLY CRITICAL CONTRIBUTION OF THE NUTRIENT DURING MAMMALIAN DEVELOPMENT. THESE INSIGHTS ALSO HIGHLIGHT A POTENTIAL RISK ASSOCIATED WITH VITAMIN C INSUFFICIENCY DURING PREGNANCY. THE LINK BETWEEN VITAMIN C INSUFFICIENCY AND DEVELOPMENT IS PARTICULARLY APPARENT IN THE CONTEXT OF NEURODEVELOPMENT AND HIGH VITAMIN C CONCENTRATIONS IN THE BRAIN ARE INDICATIVE OF IMPORTANT FUNCTIONAL REQUIREMENTS IN THIS ORGAN. ACCORDINGLY, THIS REVIEW CONSIDERS THE EVIDENCE FOR THE POTENTIAL IMPACT OF MATERNAL VITAMIN C STATUS ON NEURODEVELOPMENTAL EPIGENETICS. 2022 13 4126 40 MECHANISMS OF DISEASE: THE DEVELOPMENTAL ORIGINS OF DISEASE AND THE ROLE OF THE EPIGENOTYPE. THERE IS ACCUMULATING EVIDENCE THAT MANY CHRONIC DISEASES SUCH AS TYPE 2 DIABETES AND CORONARY HEART DISEASE MIGHT ORIGINATE DURING EARLY LIFE. THIS EVIDENCE GIVES RISE TO THE DEVELOPMENTAL ORIGINS OF DISEASE HYPOTHESIS, AND IS SUPPORTED BY EPIDEMIOLOGICAL DATA IN HUMANS AND EXPERIMENTAL ANIMAL MODELS. A PERTURBED ENVIRONMENT IN EARLY LIFE IS THOUGHT TO ELICIT A RANGE OF PHYSIOLOGICAL AND CELLULAR ADAPTIVE RESPONSES IN KEY ORGAN SYSTEMS. THESE ADAPTIVE CHANGES RESULT IN PERMANENT ALTERATIONS AND MIGHT LEAD TO PATHOLOGY IN LATER LIFE. AGING ORGANS AND CELLS SEEM THEREFORE TO RETAIN A 'MEMORY' OF THEIR FETAL HISTORY AND ADAPTIVE RESPONSES. THE MECHANISMS UNDERLYING THE DEVELOPMENTAL ORIGINS OF DISEASE REMAIN POORLY DEFINED. EPIGENETIC TAGGING OF GENES, SUCH AS DNA METHYLATION AND HISTONE MODIFICATION, CONTROLS THE FUNCTION OF THE GENOME AT DIFFERENT LEVELS AND MAINTAINS CELLULAR MEMORY AFTER MANY CELLULAR DIVISIONS; IMPORTANTLY, TAGGING CAN BE MODULATED BY THE ENVIRONMENT AND IS INVOLVED IN ONSET OF DISEASES SUCH AS CANCER. HERE WE REVIEW THE EVIDENCE FOR THE DEVELOPMENTAL ORIGINS OF DISEASE AND DISCUSS THE ROLE OF THE EPIGENOTYPE AS A CONTRIBUTING MECHANISM. ENVIRONMENTALLY INDUCED CHANGES IN THE EPIGENOTYPE MIGHT BE KEY PRIMARY EVENTS IN THE DEVELOPMENTAL ORIGINS OF DISEASE, WITH IMPORTANT CLINICAL IMPLICATIONS. 2007 14 6414 42 THE STRESSED SYNAPSE 2.0: PATHOPHYSIOLOGICAL MECHANISMS IN STRESS-RELATED NEUROPSYCHIATRIC DISORDERS. STRESS IS A PRIMARY RISK FACTOR FOR SEVERAL NEUROPSYCHIATRIC DISORDERS. EVIDENCE FROM PRECLINICAL MODELS AND CLINICAL STUDIES OF DEPRESSION HAVE REVEALED AN ARRAY OF STRUCTURAL AND FUNCTIONAL MALADAPTIVE CHANGES, WHEREBY ADVERSE ENVIRONMENTAL FACTORS SHAPE THE BRAIN. THESE CHANGES, OBSERVED FROM THE MOLECULAR AND TRANSCRIPTIONAL LEVELS THROUGH TO LARGE-SCALE BRAIN NETWORKS, TO THE BEHAVIOURS REVEAL A COMPLEX MATRIX OF INTERRELATED PATHOPHYSIOLOGICAL PROCESSES THAT DIFFER BETWEEN SEXES, PROVIDING INSIGHT INTO THE POTENTIAL UNDERPINNINGS OF THE SEX BIAS OF NEUROPSYCHIATRIC DISORDERS. ALTHOUGH MANY PRECLINICAL STUDIES USE CHRONIC STRESS PROTOCOLS, LONG-TERM CHANGES ARE ALSO INDUCED BY ACUTE EXPOSURE TO TRAUMATIC STRESS, OPENING A PATH TO IDENTIFY DETERMINANTS OF RESILIENT VERSUS SUSCEPTIBLE RESPONSES TO BOTH ACUTE AND CHRONIC STRESS. EPIGENETIC REGULATION OF GENE EXPRESSION HAS EMERGED AS A KEY PLAYER UNDERLYING THE PERSISTENT IMPACT OF STRESS ON THE BRAIN. INDEED, HISTONE MODIFICATION, DNA METHYLATION AND MICRORNAS ARE CLOSELY INVOLVED IN MANY ASPECTS OF THE STRESS RESPONSE AND REVEAL THE GLUTAMATE SYSTEM AS A KEY PLAYER. THE SUCCESS OF KETAMINE HAS STIMULATED A WHOLE LINE OF RESEARCH AND DEVELOPMENT ON DRUGS DIRECTLY OR INDIRECTLY TARGETING GLUTAMATE FUNCTION. HOWEVER, THE CHALLENGE OF TRANSLATING THE EMERGING UNDERSTANDING OF STRESS PATHOPHYSIOLOGY INTO EFFECTIVE CLINICAL TREATMENTS REMAINS A MAJOR CHALLENGE. 2022 15 679 24 BRAIN FOODS - THE ROLE OF DIET IN BRAIN PERFORMANCE AND HEALTH. THE PERFORMANCE OF THE HUMAN BRAIN IS BASED ON AN INTERPLAY BETWEEN THE INHERITED GENOTYPE AND EXTERNAL ENVIRONMENTAL FACTORS, INCLUDING DIET. FOOD AND NUTRITION, ESSENTIAL IN MAINTENANCE OF BRAIN PERFORMANCE, ALSO AID IN PREVENTION AND TREATMENT OF MENTAL DISORDERS. BOTH THE OVERALL COMPOSITION OF THE HUMAN DIET AND SPECIFIC DIETARY COMPONENTS HAVE BEEN SHOWN TO HAVE AN IMPACT ON BRAIN FUNCTION IN VARIOUS EXPERIMENTAL MODELS AND EPIDEMIOLOGICAL STUDIES. THIS NARRATIVE REVIEW PROVIDES AN OVERVIEW OF THE ROLE OF DIET IN 5 KEY AREAS OF BRAIN FUNCTION RELATED TO MENTAL HEALTH AND PERFORMANCE, INCLUDING: (1) BRAIN DEVELOPMENT, (2) SIGNALING NETWORKS AND NEUROTRANSMITTERS IN THE BRAIN, (3) COGNITION AND MEMORY, (4) THE BALANCE BETWEEN PROTEIN FORMATION AND DEGRADATION, AND (5) DETERIORATIVE EFFECTS DUE TO CHRONIC INFLAMMATORY PROCESSES. FINALLY, THE ROLE OF DIET IN EPIGENETIC REGULATION OF BRAIN PHYSIOLOGY IS DISCUSSED. 2021 16 2611 35 EPIGENETICS: A PROMISING PARADIGM FOR BETTER UNDERSTANDING AND MANAGING PAIN. EPIGENETIC REGULATION OF GENE EXPRESSION IS A RAPIDLY GROWING AREA OF RESEARCH. CONSIDERING THE LONGEVITY AND PLASTICITY OF NEURONS, THE STUDIES ON EPIGENETIC PATHWAYS IN THE NERVOUS SYSTEM SHOULD BE OF SPECIAL INTEREST FOR BOTH EPIGENETICISTS AND NEUROSCIENTISTS. ACTIVATION OR INACTIVATION OF DIFFERENT EPIGENETIC PATHWAYS BECOMES MORE PRONOUNCED WHEN THE CELLS EXPERIENCE RAPID CHANGES IN THEIR ENVIRONMENT, AND SUCH CHANGES CAN BE EASILY CAUSED BY INJURY AND INFLAMMATION, RESULTING IN PAIN PERCEPTION OR DISTORTION OF PAIN PERCEPTION (EG, HYPERALGESIA). THEREFORE, IN THIS REGARD, THE FIELD OF PAIN IS AT AN ADVANTAGE TO STUDY THE EPIGENETIC PATHWAYS. MORE IMPORTANTLY, UNDERSTANDING PAIN FROM AN EPIGENETICS POINT OF VIEW WOULD PROVIDE A NEW PARADIGM FOR DEVELOPING DRUGS OR STRATEGIES FOR PAIN MANAGEMENT. IN THIS REVIEW, WE INTRODUCE BASIC CONCEPTS OF EPIGENETICS, INCLUDING CHROMATIN DYNAMICS, HISTONE MODIFICATIONS, DNA METHYLATION, AND RNA-INDUCED GENE SILENCING. IN ADDITION, WE PROVIDE EVIDENCE FROM PUBLISHED STUDIES SUGGESTING WIDE IMPLICATION OF DIFFERENT EPIGENETIC PATHWAYS WITHIN PAIN PATHWAYS. PERSPECTIVE: THIS ARTICLE PROVIDES A BRIEF OVERVIEW OF EPIGENETIC PATHWAYS FOR GENE REGULATION AND HIGHLIGHTS THEIR INVOLVEMENT IN PAIN. OUR GOAL IS TO EXPOSE THE READERS TO THESE CONCEPTS SO THAT PAIN-RELATED PHENOTYPES CAN BE INVESTIGATED FROM THE EPIGENETIC POINT OF VIEW. 2013 17 6812 38 [EPIGENETICS, INTERFACE BETWEEN ENVIRONMENT AND GENES: ROLE IN COMPLEX DISEASES]. EPIGENETICS IS THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION OR CELLULAR PHENOTYPE CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE. EPIGENETICS IS ONE OF THE MAJOR MECHANISMS EXPLAINING THE "DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASES" (DOHAD). BESIDES GENETIC BACKGROUND INHERITED FROM PARENTS, WHICH CONFERS SUSCEPTIBILITY TO CERTAIN PATHOLOGIES, EPIGENETIC CHANGES CONSTITUTE THE MEMORY OF PREVIOUS EVENTS, EITHER POSITIVE OR NEGATIVE, ALONG THE LIFE CYCLE, INCLUDING AT THE IN UTERO STAGE. THE LATER EXPOSITION TO HOSTILE ENVIRONMENT MAY REVEAL SUCH SUSCEPTIBILITY, WITH THE DEVELOPMENT OF VARIOUS PATHOLOGIES, AMONG THEM NUMEROUS CHRONIC COMPLEX DISEASES. THE DEMONSTRATION OF SUCH A SEQUENCE OF EVENTS HAS BEEN SHOWN FOR METABOLIC DISEASES AS OBESITY, METABOLIC SYNDROME AND TYPE 2 DIABETES, CARDIOVASCULAR DISEASE AND CANCER. IN CONTRAST TO GENETIC PREDISPOSITION, WHICH IS IRREVERSIBLE, EPIGENETIC CHANGES ARE POTENTIALLY REVERSIBLE, THUS GIVING TARGETS NOT ONLY FOR PREVENTION, BUT POSSIBLY ALSO FOR THE TREATMENT OF CERTAIN COMPLEX DISEASES. 2012 18 2282 39 EPIGENETIC REGULATION IN EXPOSOME-INDUCED TUMORIGENESIS: EMERGING ROLES OF NCRNAS. ENVIRONMENTAL FACTORS, INCLUDING POLLUTANTS AND LIFESTYLE, CONSTITUTE A SIGNIFICANT ROLE IN SEVERE, CHRONIC PATHOLOGIES WITH AN ESSENTIAL SOCIETAL, ECONOMIC BURDEN. THE MEASUREMENT OF ALL ENVIRONMENTAL EXPOSURES AND ASSESSING THEIR CORRELATION WITH EFFECTS ON INDIVIDUAL HEALTH IS DEFINED AS THE EXPOSOME, WHICH INTERACTS WITH OUR UNIQUE CHARACTERISTICS SUCH AS GENETICS, PHYSIOLOGY, AND EPIGENETICS. EPIGENETICS INVESTIGATES MODIFICATIONS IN THE EXPRESSION OF GENES THAT DO NOT DEPEND ON THE UNDERLYING DNA SEQUENCE. SOME STUDIES HAVE CONFIRMED THAT ENVIRONMENTAL FACTORS MAY PROMOTE DISEASE IN INDIVIDUALS OR SUBSEQUENT PROGENY THROUGH EPIGENETIC ALTERATIONS. VARIATIONS IN THE EPIGENETIC MACHINERY CAUSE A SPECTRUM OF DIFFERENT DISORDERS SINCE THESE MECHANISMS ARE MORE SENSITIVE TO THE ENVIRONMENT THAN THE GENOME, DUE TO THE INHERENT REVERSIBLE NATURE OF THE EPIGENETIC LANDSCAPE. SEVERAL EPIGENETIC MECHANISMS, INCLUDING MODIFICATIONS IN DNA (E.G., METHYLATION), HISTONES, AND NONCODING RNAS CAN CHANGE GENOME EXPRESSION UNDER THE EXOGENOUS INFLUENCE. NOTABLY, THE ROLE OF LONG NONCODING RNAS IN EPIGENETIC PROCESSES HAS NOT BEEN WELL EXPLORED IN THE CONTEXT OF EXPOSOME-INDUCED TUMORIGENESIS. IN THE PRESENT REVIEW, OUR SCOPE IS TO PROVIDE RELEVANT EVIDENCE INDICATING THAT EPIGENETIC ALTERATIONS MEDIATE THOSE DETRIMENTAL EFFECTS CAUSED BY EXPOSURE TO ENVIRONMENTAL TOXICANTS, FOCUSING MAINLY ON A MULTI-STEP REGULATION BY DIVERSE NONCODING RNAS SUBTYPES. 2022 19 2186 48 EPIGENETIC MECHANISMS UNDERLYING PATHOBIOLOGY OF ALCOHOL USE DISORDER. PURPOSE OF REVIEW: CHRONIC ALCOHOL USE IS A WORLDWIDE PROBLEM WITH MULTIFACETED CONSEQUENCES INCLUDING MULTIPLYING MEDICAL COSTS AND SEQUELAE, SOCIETAL EFFECTS LIKE DRUNK DRIVING AND ASSAULT, AND LOST ECONOMIC PRODUCTIVITY. THESE LARGE-SCALE OUTCOMES ARE DRIVEN BY THE CONSUMPTION OF ETHANOL, A SMALL PERMEABLE MOLECULE THAT HAS MYRIAD EFFECTS IN THE HUMAN BODY, PARTICULARLY IN THE LIVER AND BRAIN. IN THIS REVIEW, WE HAVE SUMMARIZED EFFECTS OF ACUTE AND CHRONIC ALCOHOL CONSUMPTION ON EPIGENETIC MECHANISMS THAT MAY DRIVE PATHOBIOLOGY OF ALCOHOL USE DISORDER (AUD) WHILE IDENTIFYING AREAS OF NEED FOR FUTURE RESEARCH. RECENT FINDINGS: EPIGENETICS HAS EMERGED AS AN INTERESTING FIELD OF BIOLOGY AT THE INTERSECTION OF GENETICS AND THE ENVIRONMENT, AND ETHANOL IN PARTICULAR HAS BEEN IDENTIFIED AS A POTENT MODULATOR OF THE EPIGENOME WITH VARIOUS EFFECTS ON DNA METHYLATION, HISTONE MODIFICATIONS, AND NON-CODING RNAS. THESE CHANGES ALTER CHROMATIN DYNAMICS AND REGULATE GENE EXPRESSION THAT CONTRIBUTE TO BEHAVIORAL AND PHYSIOLOGICAL CHANGES LEADING TO THE DEVELOPMENT OF AUD PSYCHOPATHOLOGY AND CANCER PATHOLOGY. SUMMARY: EVIDENCE AND DISCUSSION PRESENTED HERE FROM PRECLINICAL RESULTS AND AVAILABLE TRANSLATIONAL STUDIES HAVE INCREASED OUR KNOWLEDGE OF THE EPIGENETIC EFFECTS OF ALCOHOL CONSUMPTION. THESE STUDIES HAVE IDENTIFIED TARGETS THAT CAN BE USED TO DEVELOP BETTER THERAPIES TO REDUCE CHRONIC ALCOHOL ABUSE AND MITIGATE ITS SOCIETAL BURDEN AND PATHOPHYSIOLOGY. 2020 20 2412 50 EPIGENETIC SIDE-EFFECTS OF COMMON PHARMACEUTICALS: A POTENTIAL NEW FIELD IN MEDICINE AND PHARMACOLOGY. THE TERM "EPIGENETICS" REFERS TO DNA AND CHROMATIN MODIFICATIONS THAT PERSIST FROM ONE CELL DIVISION TO THE NEXT, DESPITE A LACK OF CHANGE IN THE UNDERLYING DNA SEQUENCE. THE "EPIGENOME" REFERS TO THE OVERALL EPIGENETIC STATE OF A CELL, AND SERVES AS AN INTERFACE BETWEEN THE ENVIRONMENT AND THE GENOME. THE EPIGENOME IS DYNAMIC AND RESPONSIVE TO ENVIRONMENTAL SIGNALS NOT ONLY DURING DEVELOPMENT, BUT ALSO THROUGHOUT LIFE; AND IT IS BECOMING INCREASINGLY APPARENT THAT CHEMICALS CAN CAUSE CHANGES IN GENE EXPRESSION THAT PERSIST LONG AFTER EXPOSURE HAS CEASED. HERE WE PRESENT THE HYPOTHESIS THAT COMMONLY-USED PHARMACEUTICAL DRUGS CAN CAUSE SUCH PERSISTENT EPIGENETIC CHANGES. DRUGS MAY ALTER EPIGENETIC HOMEOSTASIS BY DIRECT OR INDIRECT MECHANISMS. DIRECT EFFECTS MAY BE CAUSED BY DRUGS WHICH AFFECT CHROMATIN ARCHITECTURE OR DNA METHYLATION. FOR EXAMPLE THE ANTIHYPERTENSIVE HYDRALAZINE INHIBITS DNA METHYLATION. AN EXAMPLE OF AN INDIRECTLY ACTING DRUG IS ISOTRETINOIN, WHICH HAS TRANSCRIPTION FACTOR ACTIVITY. A TWO-TIER MECHANISM IS POSTULATED FOR INDIRECT EFFECTS IN WHICH ACUTE EXPOSURE TO A DRUG INFLUENCES SIGNALING PATHWAYS THAT MAY LEAD TO AN ALTERATION OF TRANSCRIPTION FACTOR ACTIVITY AT GENE PROMOTERS. THIS STIMULATION RESULTS IN THE ALTERED EXPRESSION OF RECEPTORS, SIGNALING MOLECULES, AND OTHER PROTEINS NECESSARY TO ALTER GENETIC REGULATORY CIRCUITS. WITH MORE CHRONIC EXPOSURE, CELLS ADAPT BY AN UNKNOWN HYPOTHETICAL PROCESS THAT RESULTS IN MORE PERMANENT MODIFICATIONS TO DNA METHYLATION AND CHROMATIN STRUCTURE, LEADING TO ENDURING ALTERATION OF A GIVEN EPIGENETIC NETWORK. THEREFORE, ANY EPIGENETIC SIDE-EFFECT CAUSED BY A DRUG MAY PERSIST AFTER THE DRUG IS DISCONTINUED. IT IS FURTHER PROPOSED THAT SOME IATROGENIC DISEASES SUCH AS TARDIVE DYSKINESIA AND DRUG-INDUCED SLE ARE EPIGENETIC IN NATURE. IF THIS HYPOTHESIS IS CORRECT THE CONSEQUENCES FOR MODERN MEDICINE ARE PROFOUND, SINCE IT WOULD IMPLY THAT OUR CURRENT UNDERSTANDING OF PHARMACOLOGY IS AN OVERSIMPLIFICATION. WE PROPOSE THAT EPIGENETIC SIDE-EFFECTS OF PHARMACEUTICALS MAY BE INVOLVED IN THE ETIOLOGY OF HEART DISEASE, CANCER, NEUROLOGICAL AND COGNITIVE DISORDERS, OBESITY, DIABETES, INFERTILITY, AND SEXUAL DYSFUNCTION. IT IS SUGGESTED THAT A SYSTEMS BIOLOGY APPROACH EMPLOYING MICROARRAY ANALYSES OF GENE EXPRESSION AND METHYLATION PATTERNS CAN LEAD TO A BETTER UNDERSTANDING OF LONG-TERM SIDE-EFFECTS OF DRUGS, AND THAT IN THE FUTURE, EPIGENETIC ASSAYS SHOULD BE INCORPORATED INTO THE SAFETY ASSESSMENT OF ALL PHARMACEUTICAL DRUGS. THIS NEW APPROACH TO PHARMACOLOGY HAS BEEN TERMED "PHAMACOEPIGENOMICS", THE IMPACT OF WHICH MAY BE EQUAL TO OR GREATER THAN THAT OF PHARMACOGENETICS. WE PROVIDE HERE AN OVERVIEW OF THIS POTENTIALLY MAJOR NEW FIELD IN PHARMACOLOGY AND MEDICINE. 2009