1 2186 137 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 2 6324 36 THE ROLE OF ALPHA-SYNUCLEIN IN THE PATHOPHYSIOLOGY OF ALCOHOLISM. ALCOHOLISM HAS COMPLEX ETIOLOGY AND THERE IS EVIDENCE FOR BOTH GENETIC AND ENVIRONMENTAL FACTORS IN ITS PATHOPHYSIOLOGY. CHRONIC, LONG-TERM ALCOHOL ABUSE AND ALCOHOL DEPENDENCE ARE ASSOCIATED WITH NEURONAL LOSS WITH THE PREFRONTAL CORTEX BEING PARTICULARLY SUSCEPTIBLE TO NEUROTOXIC DAMAGE. THIS BRAIN REGION IS INVOLVED IN THE DEVELOPMENT AND PERSISTENCE OF ALCOHOL ADDICTION AND NEUROTOXIC DAMAGE IS LIKELY TO EXACERBATE THE REINFORCING EFFECTS OF ALCOHOL AND MAY HINDER TREATMENT. UNDERSTANDING THE MECHANISM OF ALCOHOL'S NEUROTOXIC EFFECTS ON THE BRAIN AND THE GENETIC RISK FACTORS ASSOCIATED WITH ALCOHOL ABUSE ARE THE FOCUS OF CURRENT RESEARCH. BECAUSE OF ITS WELL-ESTABLISHED ROLE IN NEURODEGENERATIVE AND NEUROPSYCHOLOGICAL DISORDERS, AND ITS EMERGING ROLE IN THE PATHOPHYSIOLOGY OF ADDICTION, HERE WE REVIEW THE GENETIC AND EPIGENETIC FACTORS INVOLVED IN REGULATING ALPHA-SYNUCLEIN EXPRESSION AND ITS POTENTIAL ROLE IN THE PATHOPHYSIOLOGY OF CHRONIC ALCOHOL ABUSE. ELUCIDATION OF THE MECHANISMS OF ALPHA-SYNUCLEIN REGULATION MAY PROVE BENEFICIAL IN UNDERSTANDING THE ROLE OF THIS KEY SYNAPTIC PROTEIN IN DISEASE AND ITS POTENTIAL FOR THERAPEUTIC MODULATION IN THE TREATMENT OF SUBSTANCE USE DISORDERS AS WELL AS OTHER NEURODEGENERATIVE DISEASES. 2013 3 3404 44 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 2235 41 EPIGENETIC MODIFICATIONS, ALCOHOLIC BRAIN AND POTENTIAL DRUG TARGETS. ACUTE AND CHRONIC ALCOHOL EXPOSURE EVIDENTLY INFLUENCES EPIGENETIC CHANGES, BOTH TRANSIENTLY AND PERMANENTLY, AND THESE CHANGES IN TURN INFLUENCE A VARIETY OF CELLS AND ORGAN SYSTEMS THROUGHOUT THE BODY. MANY OF THE ALCOHOL-INDUCED EPIGENETIC MODIFICATIONS CAN CONTRIBUTE TO CELLULAR ADAPTATIONS THAT ULTIMATELY LEAD TO BEHAVIORAL TOLERANCE AND ALCOHOL DEPENDENCE. THE PERSISTENCE OF BEHAVIORAL CHANGES DEMONSTRATES THAT LONG-LASTING CHANGES IN GENE EXPRESSION, WITHIN PARTICULAR REGIONS OF THE BRAIN, MAY CONTRIBUTE IMPORTANTLY TO THE ADDICTION PHENOTYPE. THE RESEARCH ACTIVITIES OVER THE PAST YEARS HAVE DEMONSTRATED A CRUCIAL ROLE OF EPIGENETIC MECHANISMS IN CAUSING LONG LASTING AND TRANSIENT CHANGES IN THE EXPRESSION OF SEVERAL GENES IN DIVERSE TISSUES, INCLUDING BRAIN. THIS HAS STIMULATED RECENT RESEARCH WORK THAT IS AIMED AT CHARACTERIZING THE INFLUENCE OF EPIGENETIC REGULATORY EVENTS IN MEDIATING THE LONG LASTING AND TRANSIENT EFFECTS OF ALCOHOL ABUSE ON THE BRAIN IN HUMANS AND ANIMAL MODELS OF ALCOHOL ADDICTION. IN THIS STUDY, WE UPDATE OUR CURRENT UNDERSTANDING OF THE IMPACT OF ALCOHOL EXPOSURE ON EPIGENETIC MECHANISMS IN THE BRAIN AND REFURBISH THE KNOWLEDGE OF EPIGENETICS IN THE DIRECTION OF NEW DRUGS DEVELOPMENT. 2016 5 2573 34 EPIGENETICS OF DRUG ABUSE: PREDISPOSITION OR RESPONSE. DRUG ADDICTION CONTINUES TO BE A SERIOUS MEDICAL AND SOCIAL PROBLEM. VULNERABILITY TO DEVELOP AN ADDICTION TO DRUGS IS DEPENDENT ON GENETIC, ENVIRONMENTAL, SOCIAL AND BIOLOGICAL FACTORS. IN PARTICULAR, THE INTERACTIONS OF ENVIRONMENTAL AND GENETIC FACTORS INDICATE THE SIGNIFICANCE OF EPIGENETIC MECHANISMS, WHICH HAVE BEEN FOUND TO OCCUR IN RESPONSE TO ILLICIT DRUG USE OR AS UNDERLYING FACTORS IN CHRONIC SUBSTANCE ABUSE AND RELAPSE. EPIGENETICS IS DEFINED AS THE HERITABLE AND POSSIBLY REVERSIBLE MODIFICATIONS IN GENE EXPRESSION THAT DO NOT INVOLVE ALTERATIONS IN THE DNA SEQUENCE. THIS REVIEW DISCUSSES THE VARIOUS TYPES OF EPIGENETIC MODIFICATIONS AND THEIR RELEVANCE TO DRUG ADDICTION TO ELUCIDATE WHETHER EPIGENETICS IS A PREDISPOSING FACTOR, OR A RESPONSE TO, DEVELOPING AN ADDICTION TO DRUGS OF ABUSE. 2012 6 5376 53 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 1870 53 EMERGING ROLE OF EPIGENETIC MECHANISMS IN ALCOHOL ADDICTION. ALCOHOL USE DISORDER (AUD) IS A COMPLEX BRAIN DISORDER WITH AN ARRAY OF PERSISTENT BEHAVIORAL AND NEUROCHEMICAL MANIFESTATIONS. BOTH GENETIC AND ENVIRONMENTAL FACTORS ARE KNOWN TO CONTRIBUTE TO THE DEVELOPMENT OF AUD, AND RECENT STUDIES ON ALCOHOL EXPOSURE AND SUBSEQUENT CHANGES IN GENE EXPRESSION SUGGEST THE IMPORTANCE OF EPIGENETIC MECHANISMS. IN PARTICULAR, HISTONE MODIFICATIONS AND DNA METHYLATION HAVE EMERGED AS IMPORTANT REGULATORS OF GENE EXPRESSION AND ASSOCIATED PHENOTYPES OF AUD. GIVEN THE THERAPEUTIC POTENTIAL OF EPIGENETIC TARGETS, THIS REVIEW AIMS TO SUMMARIZE THE ROLE OF EPIGENETIC REGULATION IN OUR CURRENT UNDERSTANDING OF AUD BY EVALUATING KNOWN EPIGENETIC SIGNATURES OF BRAIN REGIONS CRITICAL TO ADDICTIVE BEHAVIORS IN BOTH ANIMAL AND HUMAN STUDIES THROUGHOUT VARIOUS STAGES OF AUD. MORE SPECIFICALLY, THE EFFECTS OF ACUTE AND CHRONIC ALCOHOL EXPOSURE, TOLERANCE, AND POSTEXPOSURE WITHDRAWAL ON EPIGENETICALLY INDUCED CHANGES TO GENE EXPRESSION AND SYNAPTIC PLASTICITY WITHIN KEY BRAIN REGIONS AND THE ASSOCIATED BEHAVIORAL PHENOTYPES HAVE BEEN DISCUSSED. UNDERSTANDING THE CONTRIBUTION OF EPIGENETIC REGULATION TO CRUCIAL SIGNALING PATHWAYS MAY PROVE VITAL FOR FUTURE DEVELOPMENT OF NOVEL BIOMARKERS AND TREATMENT AGENTS IN AMELIORATING OR PREVENTING AUD. 2017 8 5930 37 TARGETING EPIGENETIC MECHANISMS TO TREAT ALCOHOL USE DISORDERS (AUD). BACKGROUND: THE IMPACT OF ABUSIVE ALCOHOL CONSUMPTION ON HUMAN HEALTH IS REMARKABLE. ACCORDING TO THE WORLD HEALTH ORGANIZATION (WHO), APPROXIMATELY 3.3 MILLION PEOPLE DIE ANNUALLY BECAUSE OF HARMFUL ALCOHOL CONSUMPTION (THE FIGURE REPRESENTS AROUND 5.9% OF GLOBAL DEATHS). ALCOHOL USE DISORDER (AUD) IS A CHRONIC DISEASE WHERE INDIVIDUALS EXHIBIT COMPULSIVE ALCOHOL DRINKING AND PRESENT NEGATIVE EMOTIONAL STATES WHEN THEY DO NOT DRINK. IN THE MOST SEVERE MANIFESTATIONS OF AUD, THE INDIVIDUALS LOSE CONTROL OVER INTAKE DESPITE A DECIDED WILL TO STOP DRINKING. GIVEN THE MULTIPLE FACES AND THE SPECIFIC FORMS OF THIS DISEASE, THE TERM AUD OFTEN APPEARS IN THE PLURAL (AUDS). SINCE ONLY A FEW APPROVED PHARMACOLOGICAL TREATMENTS ARE AVAILABLE TO TREAT AUD AND THEY DO NOT APPLY TO ALL INDIVIDUALS OR AUD FORMS, THE SEARCH FOR COMPOUNDS THAT MAY HELP TO ELIMINATE THE BURDEN OF THE DISEASE AND COMPLEMENT OTHER THERAPEUTICAL APPROACHES IS NECESSARY. METHODS: THIS WORK REVIEWS RECENT RESEARCH FOCUSED ON THE INVOLVEMENT OF EPIGENETIC MECHANISMS IN THE PATHOPHYSIOLOGY OF AUD. EXCESSIVE DRINKING LEADS TO CHRONIC AND COMPULSIVE CONSUMPTION THAT EVENTUALLY DAMAGES THE ORGANISM. THE CENTRAL NERVOUS SYSTEM IS A KEY TARGET AND IS THE FOCUS OF THIS STUDY. THE SEARCH FOR THE GENETIC AND EPIGENETIC MECHANISMS BEHIND THE INTRICATED DYSREGULATION INDUCED BY ETHANOL WILL AID RESEARCHERS IN ESTABLISHING NEW THERAPY APPROACHES. CONCLUSION: RECENT FINDINGS IN THE FIELD OF EPIGENETICS ARE ESSENTIAL AND OFFER NEW WINDOWS FOR OBSERVATION AND RESEARCH. THE STUDY OF SMALL MOLECULES THAT INHIBIT KEY EPIENZYMES INVOLVED IN NUCLEOSOME ARCHITECTURE DYNAMICS IS NECESSARY IN ORDER TO PROVE THEIR ACTION AND SPECIFICITY IN THE LABORATORY AND TO TEST THEIR EFFECTIVITY AND SAFETY IN CLINICAL TRIALS WITH SELECTED PATIENTS BEARING DEFINED ALTERATIONS CAUSED BY ETHANOL. 2021 9 2140 46 EPIGENETIC INTERACTIONS BETWEEN ALCOHOL AND CANNABINERGIC EFFECTS: FOCUS ON HISTONE MODIFICATION AND DNA METHYLATION. EPIGENETIC STUDIES HAVE LED TO A MORE PROFOUND UNDERSTANDING OF THE MECHANISMS INVOLVED IN CHRONIC CONDITIONS. IN THE CASE OF ALCOHOL ADDICTION, ACCORDING TO THE NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM, 16 MILLION ADULTS SUFFER FROM ALCOHOL USE DISORDERS (AUDS). EVEN THOUGH THERAPEUTIC INTERVENTIONS LIKE BEHAVIORAL THERAPY AND MEDICATIONS TO PREVENT RELAPSE ARE CURRENTLY AVAILABLE, NO ROBUST CURE EXISTS, WHICH STEMS FROM THE LACK OF UNDERSTANDING THE MECHANISMS OF ACTION OF ALCOHOL AND THE LACK OF DEVELOPMENT OF PRECISION MEDICINE APPROACHES TO TREAT AUDS. ANOTHER COMMON GROUP OF ADDICTIVE SUBSTANCE, CANNABINOIDS, HAVE BEEN STUDIED EXTENSIVELY TO REVEAL THEY WORK THROUGH CANNABINOID RECEPTORS. THERAPEUTIC APPLICATIONS HAVE BEEN FOUND FOR THE CANNABINOIDS AND A DEEPER UNDERSTANDING OF THE ENDOCANNABINOID SYSTEM HAS BEEN GAINED OVER THE YEARS. RECENT REPORTS OF CANNABINERGIC MECHANISMS IN AUDS HAS OPENED AN EXCITING REALM OF RESEARCH THAT SEEKS TO ELUCIDATE THE MOLECULAR MECHANISMS OF ALCOHOL-INDUCED END ORGAN DISEASES AND HOPEFULLY PROVIDE INSIGHT INTO NEW THERAPEUTIC STRATEGIES FOR THE TREATMENT OF AUDS. TO DATE, SEVERAL EPIGENETIC MECHANISMS HAVE BEEN ASSOCIATED WITH ALCOHOL AND CANNABINOIDS INDEPENDENTLY. THEREFORE, THE SCOPE OF THIS REVIEW IS TO COMPILE THE MOST RECENT LITERATURE REGARDING ALCOHOL AND CANNABINOIDS IN TERMS OF A POSSIBLE EPIGENETIC CONNECTION BETWEEN THE ENDOCANNABINOID SYSTEM AND ALCOHOL EFFECTS. FIRST, WE WILL PROVIDE AN OVERVIEW OF EPIGENETICS, FOLLOWED BY AN OVERVIEW OF ALCOHOL AND EPIGENETIC MECHANISMS WITH AN EMPHASIS ON HISTONE MODIFICATIONS AND DNA METHYLATIONS. THEN, WE WILL PROVIDE AN OVERVIEW OF CANNABINOIDS AND EPIGENETIC MECHANISMS. LASTLY, WE WILL DISCUSS EVIDENCE OF INTERACTIONS BETWEEN ALCOHOL AND CANNABINERGIC PATHWAYS AND POSSIBLE INSIGHTS INTO THE NOVEL EPIGENETIC MECHANISMS UNDERLYING ALCOHOL-CANNABINERGIC PATHWAY ACTIVITY. FINALIZING THE REVIEW WILL BE A DISCUSSION OF FUTURE DIRECTIONS AND THERAPEUTIC APPLICATIONS. 2017 10 2282 43 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 11 2154 48 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 12 2523 46 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 13 2963 26 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 14 2611 40 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 15 2333 36 EPIGENETIC REGULATION OF INFLAMMATION: THE METABOLOMICS CONNECTION. EPIGENETIC FACTORS ARE CONSIDERED THE REGULATOR OF COMPLEX MACHINERY BEHIND INFLAMMATORY DISORDERS AND SIGNIFICANTLY CONTRIBUTED TO THE EXPRESSION OF INFLAMMATION-ASSOCIATED GENES. EPIGENETIC MODIFICATIONS MODULATE VARIATION IN THE EXPRESSION PATTERN OF TARGET GENES WITHOUT AFFECTING THE DNA SEQUENCE. THE CURRENT KNOWLEDGE OF EPIGENETIC RESEARCH FOCUSED ON THEIR ROLE IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES THAT CAUSES MORBIDITY AND MORTALITY WORLDWIDE. INFLAMMATORY DISEASES ARE CATEGORIZED AS ACUTE AND CHRONIC BASED ON THE DISEASE SEVERITY AND ARE REGULATED BY THE EXPRESSION PATTERN OF VARIOUS GENES. HENCE, UNDERSTANDING THE ROLE OF EPIGENETIC MODIFICATIONS DURING INFLAMMATION PROGRESSION WILL CONTRIBUTE TO THE DISEASE OUTCOMES AND THERAPEUTIC APPROACHES. THIS REVIEW ALSO FOCUSES ON THE METABOLOMICS APPROACH ASSOCIATED WITH THE STUDY OF INFLAMMATORY DISORDERS. INFLAMMATORY RESPONSES AND METABOLIC REGULATION ARE HIGHLY INTEGRATED AND VARIOUS ADVANCED TECHNIQUES ARE ADOPTED TO STUDY THE METABOLIC SIGNATURE MOLECULES. HERE WE DISCUSS SEVERAL METABOLOMICS APPROACHES USED TO LINK INFLAMMATORY DISORDERS AND EPIGENETIC CHANGES. WE PROPOSED THAT DECIPHERING THE MECHANISM BEHIND THE INFLAMMATION-METABOLISM LOOP MAY HAVE IMMENSE IMPORTANCE IN BIOMARKERS RESEARCH AND MAY ACT AS A PRINCIPAL COMPONENT IN DRUG DISCOVERY AS WELL AS THERAPEUTIC APPLICATIONS. 2022 16 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 17 6886 42 [ROLE OF EPIGENETIC MODIFICATION IN HIGHER BRAIN DYSFUNCTION AND AGING]. EPIGENETIC MECHANISMS TYPICALLY INVOLVE HERITABLE ALTERATIONS IN CHROMATIN STRUCTURE, WHICH, IN TURN, REGULATE GENE EXPRESSION. FUNDAMENTAL INSIGHTS ABOUT EPIGENETIC HERITABILITY HAVE COME FROM STUDIES OF CELL DIVISION AND DEVELOPMENT. HOWEVER, THERE IS INCREASING EVIDENCE THAT THE REGULATION OF CHROMATIN STRUCTURE THROUGH HISTONE MODIFICATIONS AND DNA METHYLATION MIGHT MEDIATE THE EXPRESSION OF KEY GENES INVOLVED IN ACQUIRED CHRONIC DISORDERS. THIS IDEA IS FASCINATING BECAUSE SIMILAR MECHANISMS ARE USED FOR TRIGGERING AND STORING LONG-TERM MEMORIES AT THE CELLULAR LEVEL DURING, FOR EXAMPLE, HIGHER-BRAIN DYSFUNCTION, STRESS DISEASE, DRUG DEPENDENCE, AGING, AND CHRONIC PAIN. THIS REVIEW WILL EXPLORE THE MOST CURRENT ISSUES IN THE FIELD OF EPIGENETICS, WITH A FOCUS ON NEXT LEVELS OF TRANSCRIPTIONAL MECHANISMS UNDERLYING AGING, ENRICHED ENVIRONMENT AND DRUG ADDICTION. EPIGENETIC MECHANISMS, WHICH ARE KEY CELLULAR AND MOLECULAR PROCESSES THAT INTEGRATE DIVERSE ENVIRONMENTAL STIMULI TO EXERT POTENT AND OFTEN LONG-LASTING CHANGES IN GENE EXPRESSION THROUGH THE REGULATION OF CHROMATIN STRUCTURE, CONTRIBUTE TO TRANSCRIPTIONAL AND BEHAVIORAL CHANGES. 2012 18 2231 32 EPIGENETIC MODIFICATIONS OF MAJOR DEPRESSIVE DISORDER. MAJOR DEPRESSIVE DISORDER (MDD) IS A CHRONIC DISEASE WHOSE NEUROLOGICAL BASIS AND PATHOPHYSIOLOGY REMAIN POORLY UNDERSTOOD. INITIALLY, IT WAS PROPOSED THAT GENETIC VARIATIONS WERE RESPONSIBLE FOR THE DEVELOPMENT OF THIS DISEASE. NEVERTHELESS, SEVERAL STUDIES WITHIN THE LAST DECADE HAVE PROVIDED EVIDENCE SUGGESTING THAT ENVIRONMENTAL FACTORS PLAY AN IMPORTANT ROLE IN MDD PATHOPHYSIOLOGY. ALTERATIONS IN EPIGENETICS MECHANISM, SUCH AS DNA METHYLATION, HISTONE MODIFICATION AND MICRORNA EXPRESSION COULD FAVOR MDD ADVANCE IN RESPONSE TO STRESSFUL EXPERIENCES AND ENVIRONMENTAL FACTORS. THE AIM OF THIS REVIEW IS TO DESCRIBE GENETIC ALTERATIONS, AND PARTICULARLY ALTERED EPIGENETIC MECHANISMS, THAT COULD BE DETERMINANTS FOR MDD PROGRESS, AND HOW THESE ALTERATIONS MAY ARISE AS USEFUL SCREENING, DIAGNOSIS AND TREATMENT MONITORING BIOMARKERS OF DEPRESSIVE DISORDERS. 2016 19 738 35 CANCER SUSCEPTIBILITY: EPIGENETIC MANIFESTATION OF ENVIRONMENTAL EXPOSURES. CANCER IS A DISEASE THAT RESULTS FROM BOTH GENETIC AND EPIGENETIC CHANGES. DISCORDANT PHENOTYPES AND VARYING INCIDENCES OF COMPLEX DISEASES SUCH AS CANCER IN MONOZYGOTIC TWINS AS WELL AS GENETICALLY IDENTICAL LABORATORY ANIMALS HAVE LONG BEEN ATTRIBUTED TO DIFFERENCES IN ENVIRONMENTAL EXPOSURES. ACCUMULATING EVIDENCE INDICATES, HOWEVER, THAT DISPARITIES IN GENE EXPRESSION RESULTING FROM VARIABLE MODIFICATIONS IN DNA METHYLATION AND CHROMATIN STRUCTURE IN RESPONSE TO THE ENVIRONMENT ALSO PLAY A ROLE IN DIFFERENTIAL SUSCEPTIBILITY TO DISEASE. DESPITE A GROWING CONSENSUS ON THE IMPORTANCE OF EPIGENETICS IN THE ETIOLOGY OF CHRONIC HUMAN DISEASES, THE GENES MOST PRONE TO EPIGENETIC DYSREGULATION ARE INCOMPLETELY DEFINED. MOREOVER, NEITHER THE ENVIRONMENTAL AGENTS MOST STRONGLY AFFECTING THE EPIGENOME NOR THE CRITICAL WINDOWS OF VULNERABILITY TO ENVIRONMENTALLY INDUCED EPIGENETIC ALTERATIONS ARE ADEQUATELY CHARACTERIZED. THESE MAJOR DEFICITS IN KNOWLEDGE MARKEDLY IMPAIR OUR ABILITY TO UNDERSTAND FULLY THE ETIOLOGY OF CANCER AND THE IMPORTANCE OF THE EPIGENOME IN DIAGNOSING AND PREVENTING THIS DEVASTATING DISEASE. 2007 20 2567 48 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