1 6183 135 THE IMPACT OF ENVIRONMENTAL FACTORS IN INFLUENCING EPIGENETICS RELATED TO OXIDATIVE STATES IN THE CARDIOVASCULAR SYSTEM. OXIDATIVE STATES EXERT A SIGNIFICANT INFLUENCE ON A WIDE RANGE OF BIOLOGICAL AND MOLECULAR PROCESSES AND FUNCTIONS. WHEN THEIR BALANCE IS SHIFTED TOWARDS ENHANCED AMOUNTS OF FREE RADICALS, PATHOLOGICAL PHENOMENA CAN OCCUR, AS THE GENERATION OF REACTIVE OXYGEN SPECIES (ROS) IN TISSUE MICROENVIRONMENT OR IN THE SYSTEMIC CIRCULATION CAN BE DETRIMENTAL. EPIDEMIC CHRONIC DISEASES OF WESTERN SOCIETIES, SUCH AS CARDIOVASCULAR DISEASE, OBESITY, AND DIABETES CORRELATE WITH THE IMBALANCE OF REDOX HOMEOSTASIS. CURRENT ADVANCES IN OUR UNDERSTANDING OF EPIGENETICS HAVE REVEALED A PARALLEL SCENARIO SHOWING THE INFLUENCE OF OXIDATIVE STRESS AS A MAJOR REGULATOR OF EPIGENETIC GENE REGULATION VIA MODIFICATION OF DNA METHYLATION, HISTONES, AND MICRORNAS. THIS HAS PROVIDED BOTH THE BIOLOGICAL LINK AND A POTENTIAL MOLECULAR EXPLANATION BETWEEN OXIDATIVE STRESS AND CARDIOVASCULAR/METABOLIC PHENOMENA. ACCORDINGLY, IN THIS REVIEW, WE WILL PROVIDE CURRENT INSIGHTS ON THE PHYSIOLOGICAL AND PATHOLOGICAL IMPACT OF CHANGES IN OXIDATIVE STATES ON CARDIOVASCULAR DISORDERS, BY SPECIFICALLY FOCUSING ON THE INFLUENCE OF EPIGENETIC REGULATION. A SPECIAL EMPHASIS WILL HIGHLIGHT THE EFFECT ON EPIGENETIC REGULATION OF HUMAN'S CURRENT LIFE HABITS, EXTERNAL AND ENVIRONMENTAL FACTORS, INCLUDING FOOD INTAKE, TOBACCO, AIR POLLUTION, AND ANTIOXIDANT-BASED APPROACHES. ADDITIONALLY, THE STRATEGY TO QUANTIFY OXIDATIVE STATES IN HUMANS IN ORDER TO DETERMINE WHICH BIOLOGICAL MARKER COULD BEST MATCH A SUBJECT'S PROFILE WILL BE DISCUSSED. 2017 2 6034 42 THE CHALLENGE BY MULTIPLE ENVIRONMENTAL AND BIOLOGICAL FACTORS INDUCE INFLAMMATION IN AGING: THEIR ROLE IN THE PROMOTION OF CHRONIC DISEASE. THE AGING PROCESS IS DRIVEN BY MULTIPLE MECHANISMS THAT LEAD TO CHANGES IN ENERGY PRODUCTION, OXIDATIVE STRESS, HOMEOSTATIC DYSREGULATION AND EVENTUALLY TO LOSS OF FUNCTIONALITY AND INCREASED DISEASE SUSCEPTIBILITY. MOST AGED INDIVIDUALS DEVELOP CHRONIC LOW-GRADE INFLAMMATION, WHICH IS AN IMPORTANT RISK FACTOR FOR MORBIDITY, PHYSICAL AND COGNITIVE IMPAIRMENT, FRAILTY, AND DEATH. AT ANY AGE, CHRONIC INFLAMMATORY DISEASES ARE MAJOR CAUSES OF MORBIMORTALITY, AFFECTING UP TO 5-8% OF THE POPULATION OF INDUSTRIALIZED COUNTRIES. SEVERAL ENVIRONMENTAL FACTORS CAN PLAY AN IMPORTANT ROLE FOR MODIFYING THE INFLAMMATORY STATE. GENETICS ACCOUNTS FOR ONLY A SMALL FRACTION OF CHRONIC-INFLAMMATORY DISEASES, WHEREAS ENVIRONMENTAL FACTORS APPEAR TO PARTICIPATE, EITHER WITH A CAUSATIVE OR A PROMOTIONAL ROLE IN 50% TO 75% OF PATIENTS. SEVERAL OF THOSE CHANGES DEPEND ON EPIGENETIC CHANGES THAT WILL FURTHER MODIFY THE INDIVIDUAL RESPONSE TO ADDITIONAL STIMULI. THE INTERACTION BETWEEN INFLAMMATION AND THE ENVIRONMENT OFFERS IMPORTANT INSIGHTS ON AGING AND HEALTH. THESE CONDITIONS, OFTEN DEPENDING ON THE INDIVIDUAL'S SEX, APPEAR TO LEAD TO DECREASED LONGEVITY AND PHYSICAL AND COGNITIVE DECLINE. IN ADDITION TO BIOLOGICAL FACTORS, THE ENVIRONMENT IS ALSO INVOLVED IN THE GENERATION OF PSYCHOLOGICAL AND SOCIAL CONTEXT LEADING TO STRESS. POOR PSYCHOLOGICAL ENVIRONMENTS AND OTHER SOURCES OF STRESS ALSO RESULT IN INCREASED INFLAMMATION. HOWEVER, THE MECHANISMS UNDERLYING THE ROLE OF ENVIRONMENTAL AND PSYCHOSOCIAL FACTORS AND NUTRITION ON THE REGULATION OF INFLAMMATION, AND HOW THE RESPONSE ELICITED FOR THOSE FACTORS INTERACT AMONG THEM, ARE POORLY UNDERSTOOD. WHEREAS CERTAIN DELETERIOUS ENVIRONMENTAL FACTORS RESULT IN THE GENERATION OF OXIDATIVE STRESS DRIVEN BY AN INCREASED PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES, ENDOPLASMIC RETICULUM STRESS, AND INFLAMMATION, OTHER FACTORS, INCLUDING NUTRITION (POLYUNSATURATED FATTY ACIDS) AND BEHAVIORAL FACTORS (EXERCISE) CONFER PROTECTION AGAINST INFLAMMATION, OXIDATIVE AND ENDOPLASMIC RETICULUM STRESS, AND THUS AMELIORATE THEIR DELETERIOUS EFFECT. HERE, WE DISCUSS PROCESSES AND MECHANISMS OF INFLAMMATION ASSOCIATED WITH ENVIRONMENTAL FACTORS AND BEHAVIOR, THEIR LINKS TO SEX AND GENDER, AND THEIR OVERALL IMPACT ON AGING. 2020 3 5069 31 PHYSICAL ACTIVITY IN THE PREVENTION OF HUMAN DISEASES: ROLE OF EPIGENETIC MODIFICATIONS. EPIGENETIC MODIFICATION REFERS TO HERITABLE CHANGES IN GENE FUNCTION THAT CANNOT BE EXPLAINED BY ALTERATIONS IN THE DNA SEQUENCE. THE CURRENT LITERATURE CLEARLY DEMONSTRATES THAT THE EPIGENETIC RESPONSE IS HIGHLY DYNAMIC AND INFLUENCED BY DIFFERENT BIOLOGICAL AND ENVIRONMENTAL FACTORS SUCH AS AGING, NUTRIENT AVAILABILITY AND PHYSICAL EXERCISE. AS SUCH, IT IS WELL ACCEPTED THAT PHYSICAL ACTIVITY AND EXERCISE CAN MODULATE GENE EXPRESSION THROUGH EPIGENETIC ALTERNATIONS ALTHOUGH THE TYPE AND DURATION OF EXERCISE ELICITING SPECIFIC EPIGENETIC EFFECTS THAT CAN RESULT IN HEALTH BENEFITS AND PREVENT CHRONIC DISEASES REMAINS TO BE DETERMINED. THIS REVIEW HIGHLIGHTS THE MOST SIGNIFICANT FINDINGS FROM EPIGENETIC STUDIES INVOLVING PHYSICAL ACTIVITY/EXERCISE INTERVENTIONS KNOWN TO BENEFIT CHRONIC DISEASES SUCH AS METABOLIC SYNDROME, DIABETES, CANCER, CARDIOVASCULAR AND NEURODEGENERATIVE DISEASES. 2017 4 4273 39 MICROBIOTA AND EPIGENETICS: HEALTH IMPACT. EPIGENETIC CHANGES ASSOCIATED WITH DISEASE DEVELOPMENT AND PROGRESSIONS ARE OF INCREASING IMPORTANCE BECAUSE OF THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. SEVERAL EPIGENETIC CHANGES ASSOCIATED WITH CHRONIC METABOLIC DISORDERS HAVE BEEN STUDIED IN VARIOUS DISEASES. EPIGENETIC CHANGES ARE MOSTLY MODULATED BY ENVIRONMENTAL FACTORS, INCLUDING THE HUMAN MICROBIOTA LIVING IN DIFFERENT PARTS OF OUR BODIES. THE MICROBIAL STRUCTURAL COMPONENTS AND THE MICROBIALLY DERIVED METABOLITES DIRECTLY INTERACT WITH HOST CELLS, THEREBY MAINTAINING HOMEOSTASIS. MICROBIOME DYSBIOSIS, ON THE OTHER HAND, IS KNOWN TO PRODUCE ELEVATED LEVELS OF DISEASE-LINKED METABOLITES, WHICH MAY DIRECTLY AFFECT A HOST METABOLIC PATHWAY OR INDUCE EPIGENETIC CHANGES THAT CAN LEAD TO DISEASE DEVELOPMENT. DESPITE THEIR IMPORTANT ROLE IN HOST PHYSIOLOGY AND SIGNAL TRANSDUCTION, THERE HAS BEEN LITTLE RESEARCH INTO THE MECHANICS AND PATHWAYS ASSOCIATED WITH EPIGENETIC MODIFICATIONS. THIS CHAPTER FOCUSES ON THE RELATIONSHIP BETWEEN MICROBES AND THEIR EPIGENETIC EFFECTS IN DISEASED PATHOLOGY, AS WELL AS ON THE REGULATION AND METABOLISM OF THE DIETARY OPTIONS AVAILABLE TO THE MICROBES. FURTHERMORE, THIS CHAPTER ALSO PROVIDES A PROSPECTIVE LINK BETWEEN THESE TWO IMPORTANT PHENOMENA, TERMED "MICROBIOME AND EPIGENETICS." 2023 5 6287 34 THE POTENTIAL ROLE OF ENVIRONMENTAL FACTORS IN MODULATING MITOCHONDRIAL DNA EPIGENETIC MARKS. MANY STUDIES IMPLICATE MITOCHONDRIAL DYSFUNCTION IN THE DEVELOPMENT AND PROGRESSION OF NUMEROUS CHRONIC DISEASES. MITOCHONDRIA ARE RESPONSIBLE FOR MOST CELLULAR ENERGY PRODUCTION, AND UNLIKE OTHER CYTOPLASMIC ORGANELLES, MITOCHONDRIA CONTAIN THEIR OWN GENOME. MOST RESEARCH TO DATE, THROUGH INVESTIGATING MITOCHONDRIAL DNA COPY NUMBER, HAS FOCUSED ON LARGER STRUCTURAL CHANGES OR ALTERATIONS TO THE ENTIRE MITOCHONDRIAL GENOME AND THEIR ROLE IN HUMAN DISEASE. USING THESE METHODS, MITOCHONDRIAL DYSFUNCTION HAS BEEN LINKED TO CANCERS, CARDIOVASCULAR DISEASE, AND METABOLIC HEALTH. HOWEVER, LIKE THE NUCLEAR GENOME, THE MITOCHONDRIAL GENOME MAY EXPERIENCE EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION THAT MAY PARTIALLY EXPLAIN SOME OF THE HEALTH EFFECTS OF VARIOUS EXPOSURES. RECENTLY, THERE HAS BEEN A MOVEMENT TO UNDERSTAND HUMAN HEALTH AND DISEASE WITHIN THE CONTEXT OF THE EXPOSOME, WHICH AIMS TO DESCRIBE AND QUANTIFY THE ENTIRETY OF ALL EXPOSURES PEOPLE ENCOUNTER THROUGHOUT THEIR LIVES. THESE INCLUDE, AMONG OTHERS, ENVIRONMENTAL POLLUTANTS, OCCUPATIONAL EXPOSURES, HEAVY METALS, AND LIFESTYLE AND BEHAVIORAL FACTORS. IN THIS CHAPTER, WE SUMMARIZE THE CURRENT RESEARCH ON MITOCHONDRIA AND HUMAN HEALTH, PROVIDE AN OVERVIEW OF THE CURRENT KNOWLEDGE ON MITOCHONDRIAL EPIGENETICS, AND DESCRIBE THE EXPERIMENTAL AND EPIDEMIOLOGIC STUDIES THAT HAVE INVESTIGATED PARTICULAR EXPOSURES AND THEIR RELATIONSHIPS WITH MITOCHONDRIAL EPIGENETIC MODIFICATIONS. WE CONCLUDE THE CHAPTER WITH SUGGESTIONS FOR FUTURE DIRECTIONS IN EPIDEMIOLOGIC AND EXPERIMENTAL RESEARCH THAT IS NEEDED TO ADVANCE THE GROWING FIELD OF MITOCHONDRIAL EPIGENETICS. 2023 6 5821 38 STRESS IN OBESITY AND ASSOCIATED METABOLIC AND CARDIOVASCULAR DISORDERS. OBESITY HAS SIGNIFICANT IMPLICATIONS FOR HEALTHCARE, SINCE IT IS A MAJOR RISK FACTOR FOR BOTH TYPE 2 DIABETES AND THE METABOLIC SYNDROME. THIS SYNDROME IS A COMMON AND COMPLEX DISORDER COMBINING OBESITY, DYSLIPIDEMIA, HYPERTENSION, AND INSULIN RESISTANCE. IT IS ASSOCIATED WITH HIGH ATHEROSCLEROTIC CARDIOVASCULAR RISK, WHICH CAN ONLY PARTIALLY BE EXPLAINED BY ITS COMPONENTS. THEREFORE, TO EXPLAIN HOW OBESITY CONTRIBUTES TO THE DEVELOPMENT OF METABOLIC AND CARDIOVASCULAR DISORDERS, MORE AND BETTER INSIGHT IS REQUIRED INTO THE EFFECTS OF PERSONAL AND ENVIRONMENTAL STRESS ON DISEASE PROCESSES. IN THIS PAPER, WE SHOW THAT OBESITY IS A CHRONIC INFLAMMATORY DISEASE, WHICH HAS MANY MOLECULAR MECHANISMS IN COMMON WITH ATHEROSCLEROSIS. FURTHERMORE, WE FOCUS ON THE ROLE OF OXIDATIVE STRESS ASSOCIATED WITH OBESITY IN THE DEVELOPMENT OF THE METABOLIC SYNDROME. WE DISCUSS HOW SEVERAL STRESS CONDITIONS ARE RELATED TO INFLAMMATION AND OXIDATIVE STRESS IN ASSOCIATION WITH OBESITY AND ITS COMPLICATIONS. WE ALSO EMPHASIZE THE RELATION BETWEEN STRESS CONDITIONS AND THE DEREGULATION OF EPIGENETIC CONTROL MECHANISMS BY MEANS OF MICRORNAS AND SHOW HOW THIS IMPAIRMENT FURTHER CONTRIBUTES TO THE DEVELOPMENT OF OBESITY, CLOSING THE VICIOUS CIRCLE. FINALLY, WE DISCUSS THE LIMITATIONS OF CURRENT ANTI-INFLAMMATION AND ANTIOXIDANT THERAPY TO TREAT OBESITY. 2012 7 2562 29 EPIGENETICS IN THE PRIMARY AND SECONDARY PREVENTION OF CARDIOVASCULAR DISEASE: INFLUENCE OF EXERCISE AND NUTRITION. INCREASING EVIDENCE LINKS CHANGES IN EPIGENETIC SYSTEMS, SUCH AS DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA EXPRESSION, TO THE OCCURRENCE OF CARDIOVASCULAR DISEASE (CVD). THESE EPIGENETIC MODIFICATIONS CAN CHANGE GENETIC FUNCTION UNDER INFLUENCE OF EXOGENOUS STIMULI AND CAN BE TRANSFERRED TO NEXT GENERATIONS, PROVIDING A POTENTIAL MECHANISM FOR INHERITANCE OF BEHAVIOURAL INTERVENTION EFFECTS. THE BENEFITS OF EXERCISE AND NUTRITIONAL INTERVENTIONS IN THE PRIMARY AND SECONDARY PREVENTION OF CVD ARE WELL ESTABLISHED, BUT THE MECHANISMS ARE NOT COMPLETELY UNDERSTOOD. IN THIS REVIEW, WE DESCRIBE THE ACUTE AND CHRONIC EPIGENETIC EFFECTS OF PHYSICAL ACTIVITY AND DIETARY CHANGES. WE PROPOSE EXERCISE AND NUTRITION AS POTENTIAL TRIGGERS OF EPIGENETIC SIGNALS, PROMOTING THE RESHAPING OF TRANSCRIPTIONAL PROGRAMMES WITH EFFECTS ON CVD PHENOTYPES. FINALLY, WE HIGHLIGHT RECENT DEVELOPMENTS IN EPIGENETIC THERAPEUTICS WITH IMPLICATIONS FOR PRIMARY AND SECONDARY CVD PREVENTION. 2022 8 2855 51 FROM INFLAMMAGING TO HEALTHY AGING BY DIETARY LIFESTYLE CHOICES: IS EPIGENETICS THE KEY TO PERSONALIZED NUTRITION? THE PROGRESSIVELY OLDER POPULATION IN DEVELOPED COUNTRIES IS REFLECTED IN AN INCREASE IN THE NUMBER OF PEOPLE SUFFERING FROM AGE-RELATED CHRONIC INFLAMMATORY DISEASES SUCH AS METABOLIC SYNDROME, DIABETES, HEART AND LUNG DISEASES, CANCER, OSTEOPOROSIS, ARTHRITIS, AND DEMENTIA. THE HETEROGENEITY IN BIOLOGICAL AGING, CHRONOLOGICAL AGE, AND AGING-ASSOCIATED DISORDERS IN HUMANS HAVE BEEN ASCRIBED TO DIFFERENT GENETIC AND ENVIRONMENTAL FACTORS (I.E., DIET, POLLUTION, STRESS) THAT ARE CLOSELY LINKED TO SOCIOECONOMIC FACTORS. THE COMMON DENOMINATOR OF THESE FACTORS IS THE INFLAMMATORY RESPONSE. CHRONIC LOW-GRADE SYSTEMIC INFLAMMATION DURING PHYSIOLOGICAL AGING AND IMMUNOSENESCENCE ARE INTERTWINED IN THE PATHOGENESIS OF PREMATURE AGING ALSO DEFINED AS 'INFLAMMAGING.' THE LATTER HAS BEEN ASSOCIATED WITH FRAILTY, MORBIDITY, AND MORTALITY IN ELDERLY SUBJECTS. HOWEVER, IT IS UNKNOWN TO WHAT EXTENT INFLAMMAGING OR LONGEVITY IS CONTROLLED BY EPIGENETIC EVENTS IN EARLY LIFE. TODAY, HUMAN DIET IS BELIEVED TO HAVE A MAJOR INFLUENCE ON BOTH THE DEVELOPMENT AND PREVENTION OF AGE-RELATED DISEASES. MOST PLANT-DERIVED DIETARY PHYTOCHEMICALS AND MACRO- AND MICRONUTRIENTS MODULATE OXIDATIVE STRESS AND INFLAMMATORY SIGNALING AND REGULATE METABOLIC PATHWAYS AND BIOENERGETICS THAT CAN BE TRANSLATED INTO STABLE EPIGENETIC PATTERNS OF GENE EXPRESSION. THEREFORE, DIET INTERVENTIONS DESIGNED FOR HEALTHY AGING HAVE BECOME A HOT TOPIC IN NUTRITIONAL EPIGENOMIC RESEARCH. INCREASING EVIDENCE HAS REVEALED THAT COMPLEX INTERACTIONS BETWEEN FOOD COMPONENTS AND HISTONE MODIFICATIONS, DNA METHYLATION, NON-CODING RNA EXPRESSION, AND CHROMATIN REMODELING FACTORS INFLUENCE THE INFLAMMAGING PHENOTYPE AND AS SUCH MAY PROTECT OR PREDISPOSE AN INDIVIDUAL TO MANY AGE-RELATED DISEASES. REMARKABLY, HUMANS PRESENT A BROAD RANGE OF RESPONSES TO SIMILAR DIETARY CHALLENGES DUE TO BOTH GENETIC AND EPIGENETIC MODULATIONS OF THE EXPRESSION OF TARGET PROTEINS AND KEY GENES INVOLVED IN THE METABOLISM AND DISTRIBUTION OF THE DIETARY CONSTITUENTS. HERE, WE WILL SUMMARIZE THE EPIGENETIC ACTIONS OF DIETARY COMPONENTS, INCLUDING PHYTOCHEMICALS, AND MACRO- AND MICRONUTRIENTS AS WELL AS METABOLITES, THAT CAN ATTENUATE INFLAMMAGING. WE WILL DISCUSS THE CHALLENGES FACING PERSONALIZED NUTRITION TO TRANSLATE HIGHLY VARIABLE INTERINDIVIDUAL EPIGENETIC DIET RESPONSES TO POTENTIAL INDIVIDUAL HEALTH BENEFITS/RISKS RELATED TO AGING DISEASE. 2015 9 4460 38 MOLECULAR MECHANISMS OF ENVIRONMENTAL EXPOSURES AND HUMAN DISEASE. A SUBSTANTIAL PROPORTION OF DISEASE RISK FOR COMMON COMPLEX DISORDERS IS ATTRIBUTABLE TO ENVIRONMENTAL EXPOSURES AND POLLUTANTS. AN APPRECIATION OF HOW ENVIRONMENTAL POLLUTANTS ACT ON OUR CELLS TO PRODUCE DELETERIOUS HEALTH EFFECTS HAS LED TO ADVANCES IN OUR UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING THE PATHOGENESIS OF CHRONIC DISEASES, INCLUDING CANCER AND CARDIOVASCULAR, NEURODEGENERATIVE AND RESPIRATORY DISEASES. HERE, WE DISCUSS EMERGING RESEARCH ON THE INTERPLAY OF ENVIRONMENTAL POLLUTANTS WITH THE HUMAN GENOME AND EPIGENOME. WE REVIEW EVIDENCE SHOWING THE ENVIRONMENTAL IMPACT ON GENE EXPRESSION THROUGH EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND NON-CODING RNAS. WE ALSO HIGHLIGHT RECENT STUDIES THAT EVALUATE RECENTLY DISCOVERED MOLECULAR PROCESSES THROUGH WHICH THE ENVIRONMENT CAN EXERT ITS EFFECTS, INCLUDING EXTRACELLULAR VESICLES, THE EPITRANSCRIPTOME AND THE MITOCHONDRIAL GENOME. FINALLY, WE DISCUSS CURRENT CHALLENGES WHEN STUDYING THE EXPOSOME - THE CUMULATIVE MEASURE OF ENVIRONMENTAL INFLUENCES OVER THE LIFESPAN - AND ITS INTEGRATION INTO FUTURE ENVIRONMENTAL HEALTH RESEARCH. 2023 10 3404 33 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 11 6812 31 [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 12 6204 42 THE INFLUENCE OF EPIGENETICS AND INFLAMMATION ON CARDIOMETABOLIC RISKS. CARDIOMETABOLIC DISEASES INCLUDE METABOLIC SYNDROME, OBESITY, TYPE 2 DIABETES MELLITUS, AND HYPERTENSION. EPIGENETIC MODIFICATIONS PARTICIPATE IN CARDIOMETABOLIC DISEASES THROUGH SEVERAL PATHWAYS, INCLUDING INFLAMMATION, VASCULAR DYSFUNCTION, AND INSULIN RESISTANCE. EPIGENETIC MODIFICATIONS, WHICH ENCOMPASS ALTERATIONS TO GENE EXPRESSION WITHOUT MUTATING THE DNA SEQUENCE, HAVE GAINED MUCH ATTENTION IN RECENT YEARS, SINCE THEY HAVE BEEN CORRELATED WITH CARDIOMETABOLIC DISEASES AND MAY BE TARGETED FOR THERAPEUTIC INTERVENTIONS. EPIGENETIC MODIFICATIONS ARE GREATLY INFLUENCED BY ENVIRONMENTAL FACTORS, SUCH AS DIET, PHYSICAL ACTIVITY, CIGARETTE SMOKING, AND POLLUTION. SOME MODIFICATIONS ARE HERITABLE, INDICATING THAT THE BIOLOGICAL EXPRESSION OF EPIGENETIC ALTERATIONS MAY BE OBSERVED ACROSS GENERATIONS. MOREOVER, MANY PATIENTS WITH CARDIOMETABOLIC DISEASES PRESENT WITH CHRONIC INFLAMMATION, WHICH CAN BE INFLUENCED BY ENVIRONMENTAL AND GENETIC FACTORS. THE INFLAMMATORY ENVIRONMENT WORSENS THE PROGNOSIS OF CARDIOMETABOLIC DISEASES AND FURTHER INDUCES EPIGENETIC MODIFICATIONS, PREDISPOSING PATIENTS TO THE DEVELOPMENT OF OTHER METABOLISM-ASSOCIATED DISEASES AND COMPLICATIONS. A DEEPER UNDERSTANDING OF INFLAMMATORY PROCESSES AND EPIGENETIC MODIFICATIONS IN CARDIOMETABOLIC DISEASES IS NECESSARY TO IMPROVE OUR DIAGNOSTIC CAPABILITIES, PERSONALIZED MEDICINE APPROACHES, AND THE DEVELOPMENT OF TARGETED THERAPEUTIC INTERVENTIONS. FURTHER UNDERSTANDING MAY ALSO ASSIST IN PREDICTING DISEASE OUTCOMES, ESPECIALLY IN CHILDREN AND YOUNG ADULTS. THIS REVIEW DESCRIBES EPIGENETIC MODIFICATIONS AND INFLAMMATORY PROCESSES UNDERLYING CARDIOMETABOLIC DISEASES, AND FURTHER DISCUSSES ADVANCES IN THE RESEARCH FIELD WITH A FOCUS ON SPECIFIC POINTS FOR INTERVENTIONAL THERAPY. 2023 13 6715 42 VITAMIN A AND THE EPIGENOME. THE EPIGENETIC PHENOMENA REFER TO HERITABLE CHANGES IN GENE EXPRESSION OTHER THAN THOSE IN THE DNA SEQUENCE, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS. MAJOR RESEARCH PROGRESS IN THE LAST FEW YEARS HAS PROVIDED FURTHER PROOF THAT ENVIRONMENTAL FACTORS, INCLUDING DIET AND NUTRITION, CAN INFLUENCE PHYSIOLOGIC AND PATHOLOGIC PROCESSES THROUGH EPIGENETIC ALTERATIONS, WHICH IN TURN INFLUENCE GENE EXPRESSION. THIS INFLUENCE IS TERMED NUTRITIONAL EPIGENETICS, AND ONE PROMINENT EXAMPLE IS THE REGULATION OF GENE TRANSCRIPTION BY VITAMIN A THROUGH INTERACTION TO ITS NUCLEAR RECEPTOR. VITAMIN A IS CRITICAL THROUGHOUT LIFE. TOGETHER WITH ITS DERIVATIVES, IT REGULATES DIVERSE PROCESSES INCLUDING REPRODUCTION, EMBRYOGENESIS, VISION, GROWTH, CELLULAR DIFFERENTIATION AND PROLIFERATION, MAINTENANCE OF EPITHELIAL CELLULAR INTEGRITY AND IMMUNE FUNCTION. HERE WE REVIEW THE EPIGENETIC ROLE OF VITAMIN A IN CANCER, STEM CELLS DIFFERENTIATION, PROLIFERATION, AND IMMUNITY. THE DATA PRESENTED HERE SHOW THAT RETINOIC ACID IS A POTENT AGENT CAPABLE OF INDUCING ALTERATIONS IN EPIGENETIC MODIFICATIONS THAT PRODUCE VARIOUS EFFECTS ON THE PHENOTYPE. MEDICAL BENEFITS OF VITAMIN A AS AN EPIGENETIC MODULATOR, ESPECIALLY WITH RESPECT TO ITS CHRONIC USE AS NUTRITIONAL SUPPLEMENT, SHOULD RELY ON OUR FURTHER UNDERSTANDING OF ITS EPIGENETIC EFFECTS DURING HEALTH AND DISEASE, AS WELL AS THROUGH DIFFERENT GENERATIONS. 2017 14 5076 36 PHYSIOLOGICAL AND ENVIRONMENTAL FACTORS AFFECTING CANCER RISK AND PROGNOSIS IN OBESITY. OBESITY RESULTS FROM A CHRONIC EXCESSIVE ACCUMULATION OF ADIPOSE TISSUE DUE TO A LONG-TERM IMBALANCE BETWEEN ENERGY INTAKE AND EXPENDITURE. AVAILABLE EPIDEMIOLOGICAL AND CLINICAL DATA STRONGLY SUPPORT THE LINKS BETWEEN OBESITY AND CERTAIN CANCERS. EMERGING CLINICAL AND EXPERIMENTAL FINDINGS HAVE IMPROVED OUR UNDERSTANDING OF THE ROLES OF KEY PLAYERS IN OBESITY-ASSOCIATED CARCINOGENESIS SUCH AS AGE, SEX (MENOPAUSE), GENETIC AND EPIGENETIC FACTORS, GUT MICROBIOTA AND METABOLIC FACTORS, BODY SHAPE TRAJECTORY OVER LIFE, DIETARY HABITS, AND GENERAL LIFESTYLE. IT IS NOW WIDELY ACCEPTED THAT THE CANCER-OBESITY RELATIONSHIP DEPENDS ON THE SITE OF CANCER, THE SYSTEMIC INFLAMMATORY STATUS, AND MICRO ENVIRONMENTAL PARAMETERS SUCH AS LEVELS OF INFLAMMATION AND OXIDATIVE STRESS IN TRANSFORMING TISSUES. WE HEREBY REVIEW RECENT ADVANCES IN OUR UNDERSTANDING OF CANCER RISK AND PROGNOSIS IN OBESITY WITH RESPECT TO THESE PLAYERS. WE HIGHLIGHT HOW THE LACK OF THEIR CONSIDERATION CONTRIBUTED TO THE CONTROVERSY OVER THE LINK BETWEEN OBESITY AND CANCER IN EARLY EPIDEMIOLOGICAL STUDIES. FINALLY, THE LESSONS AND CHALLENGES OF INTERVENTIONS FOR WEIGHT LOSS AND BETTER CANCER PROGNOSIS, AND THE MECHANISMS OF WEIGHT GAIN IN SURVIVORS ARE ALSO DISCUSSED. 2023 15 2282 41 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 16 996 35 CHRONIC STRESS, EPIGENETICS, AND ADIPOSE TISSUE METABOLISM IN THE OBESE STATE. IN OBESITY, ENDOCRINE AND METABOLIC PERTURBATIONS, INCLUDING THOSE INDUCED BY CHRONIC ACTIVATION OF THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS, ARE ASSOCIATED WITH THE ACCUMULATION OF ADIPOSE TISSUE AND INFLAMMATION. SUCH CHANGES ARE ATTRIBUTABLE TO A COMBINATION OF GENETIC AND EPIGENETIC FACTORS THAT ARE INFLUENCED BY THE ENVIRONMENT AND EXACERBATED BY CHRONIC ACTIVATION OF THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS. STRESS EXPOSURE AT DIFFERENT LIFE STAGES CAN ALTER ADIPOSE TISSUE METABOLISM DIRECTLY THROUGH EPIGENETIC MODIFICATION OR INDIRECTLY THROUGH THE MANIPULATION OF HYPOTHALAMIC APPETITE REGULATION, AND THEREBY CONTRIBUTE TO ENDOCRINE CHANGES THAT FURTHER DISRUPT WHOLE-BODY ENERGY BALANCE. THIS REVIEW SYNTHESIZES CURRENT KNOWLEDGE, WITH AN EMPHASIS ON HUMAN CLINICAL TRIALS, TO DESCRIBE METABOLIC CHANGES IN ADIPOSE TISSUE AND ASSOCIATED ENDOCRINE, GENETIC AND EPIGENETIC CHANGES IN THE OBESE STATE. IN PARTICULAR, WE DISCUSS EPIGENETIC CHANGES INDUCED BY STRESS EXPOSURE AND THEIR CONTRIBUTION TO APPETITE AND ADIPOCYTE DYSFUNCTION, WHICH COLLECTIVELY PROMOTE THE PATHOGENESIS OF OBESITY. SUCH KNOWLEDGE IS CRITICAL FOR PROVIDING FUTURE DIRECTIONS OF METABOLISM RESEARCH AND TARGETS FOR TREATING METABOLIC DISORDERS. 2020 17 6211 37 THE INTERPLAY BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN IN HEALTH AND DISEASE: POTENTIAL ROLE OF AUTONOMIC REGULATION AND EPIGENETIC MECHANISMS. OXIDATIVE STRESS CAN BE INDUCED BY VARIOUS STIMULI AND ALTERED IN CERTAIN CONDITIONS, INCLUDING EXERCISE AND PAIN. ALTHOUGH MANY STUDIES HAVE INVESTIGATED OXIDATIVE STRESS IN RELATION TO EITHER EXERCISE OR PAIN, THE LITERATURE PRESENTS CONFLICTING RESULTS. THEREFORE, THIS REVIEW CRITICALLY DISCUSSES EXISTING LITERATURE ABOUT THIS TOPIC, AIMING TO PROVIDE A CLEAR OVERVIEW OF KNOWN INTERACTIONS BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN IN HEALTHY PEOPLE AS WELL AS IN PEOPLE WITH CHRONIC PAIN, AND TO HIGHLIGHT POSSIBLE CONFOUNDING FACTORS TO KEEP IN MIND WHEN REFLECTING ON THESE INTERACTIONS. IN ADDITION, AUTONOMIC REGULATION AND EPIGENETIC MECHANISMS ARE PROPOSED AS POTENTIAL MECHANISMS OF ACTION UNDERLYING THE INTERPLAY BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN. THIS REVIEW HIGHLIGHTS THAT THE RELATION BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN IS POORLY UNDERSTOOD AND NOT STRAIGHTFORWARD, AS IT IS DEPENDENT ON THE CHARACTERISTICS OF EXERCISE, BUT ALSO ON WHICH POPULATION IS INVESTIGATED. TO BE ABLE TO COMPARE STUDIES ON THIS TOPIC, STRICT GUIDELINES SHOULD BE DEVELOPED TO LIMIT THE EFFECT OF SEVERAL CONFOUNDING FACTORS. THIS WAY, THE TRUE INTERPLAY BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN, AND THE UNDERLYING MECHANISMS OF ACTION CAN BE REVEALED AND VALIDATED VIA INDEPENDENT STUDIES. 2020 18 2930 34 GENES AND DIET IN THE PREVENTION OF CHRONIC DISEASES IN FUTURE GENERATIONS. NUTRITION IS A MODIFIABLE KEY FACTOR THAT IS ABLE TO INTERACT WITH BOTH THE GENOME AND EPIGENOME TO INFLUENCE HUMAN HEALTH AND FERTILITY. IN PARTICULAR, SPECIFIC GENETIC VARIANTS CAN INFLUENCE THE RESPONSE TO DIETARY COMPONENTS AND NUTRIENT REQUIREMENTS, AND CONVERSELY, THE DIET ITSELF IS ABLE TO MODULATE GENE EXPRESSION. IN THIS CONTEXT AND THE ERA OF PRECISION MEDICINE, NUTRIGENETIC AND NUTRIGENOMIC STUDIES OFFER SIGNIFICANT OPPORTUNITIES TO IMPROVE THE PREVENTION OF METABOLIC DISTURBANCES, SUCH AS TYPE 2 DIABETES, GESTATIONAL DIABETES, HYPERTENSION, AND CARDIOVASCULAR DISEASES, EVEN WITH TRANSGENERATIONAL EFFECTS. THE PRESENT REVIEW TAKES INTO ACCOUNT THE INTERACTIONS BETWEEN DIET, GENES AND HUMAN HEALTH, AND PROVIDES AN OVERVIEW OF THE ROLE OF NUTRIGENETICS, NUTRIGENOMICS AND EPIGENETICS IN THE PREVENTION OF NON-COMMUNICABLE DISEASES. MOREOVER, WE FOCUS OUR ATTENTION ON THE MECHANISM OF INTERGENERATIONAL OR TRANSGENERATIONAL TRANSMISSION OF THE SUSCEPTIBILITY TO METABOLIC DISTURBANCES, AND UNDERLINE THAT THE REVERSIBILITY OF EPIGENETIC MODIFICATIONS THROUGH DIETARY INTERVENTION COULD COUNTERACT PERTURBATIONS INDUCED BY LIFESTYLE AND ENVIRONMENTAL FACTORS. 2020 19 1360 41 DEVELOPMENTAL ASPECTS OF A LIFE COURSE APPROACH TO HEALTHY AGEING. WE EXAMINE THE MECHANISTIC BASIS AND WIDER IMPLICATIONS OF ADOPTING A DEVELOPMENTAL PERSPECTIVE ON HUMAN AGEING. PREVIOUS MODELS OF AGEING HAVE CONCENTRATED ON ITS GENETIC BASIS, OR THE DETRIMENTAL EFFECTS OF ACCUMULATED DAMAGE, BUT ALSO HAVE RAISED ISSUES ABOUT WHETHER AGEING CAN BE VIEWED AS ADAPTIVE ITSELF, OR IS A CONSEQUENCE OF OTHER ADAPTIVE PROCESSES, FOR EXAMPLE IF MAINTENANCE AND REPAIR PROCESSES IN THE PERIOD UP TO REPRODUCTION ARE TRADED OFF AGAINST LATER DECLINE IN FUNCTION. A LIFE COURSE MODEL PLACES AGEING IN THE CONTEXT OF THE ATTAINMENT OF PEAK CAPACITY FOR A BODY SYSTEM, STARTING IN EARLY DEVELOPMENT WHEN PLASTICITY PERMITS CHANGES IN STRUCTURE AND FUNCTION INDUCED BY A RANGE OF ENVIRONMENTAL STIMULI, FOLLOWED BY A PERIOD OF DECLINE, THE RATE OF WHICH DEPENDS ON THE PEAK ATTAINED AS WELL AS THE LATER LIFE CONDITIONS. SUCH PATH DEPENDENCY IN THE RATE OF AGEING MAY OFFER NEW INSIGHTS INTO ITS MODIFICATION. FOCUSING ON MUSCULOSKELETAL AND CARDIOVASCULAR FUNCTION, WE DISCUSS THIS MODEL AND THE POSSIBLE UNDERLYING MECHANISMS, INCLUDING ENDOTHELIAL FUNCTION, OXIDATIVE STRESS, STEM CELLS AND NUTRITIONAL FACTORS SUCH AS VITAMIN D STATUS. EPIGENETIC CHANGES INDUCED DURING DEVELOPMENTAL PLASTICITY, AND IMMUNE FUNCTION MAY PROVIDE A COMMON MECHANISTIC PROCESS UNDERLYING A LIFE COURSE MODEL OF AGEING. THE LIFE COURSE TRAJECTORY DIFFERS IN HIGH AND LOW RESOURCE SETTINGS. NEW INSIGHTS INTO THE DEVELOPMENTAL COMPONENTS OF THE LIFE COURSE MODEL OF AGEING MAY LEAD TO THE DESIGN OF BIOMARKERS OF LATER CHRONIC DISEASE RISK AND TO NEW INTERVENTIONS TO PROMOTE HEALTHY AGEING, WITH IMPORTANT IMPLICATIONS FOR PUBLIC HEALTH. 2016 20 2163 33 EPIGENETIC MECHANISMS IN DIABETIC VASCULAR COMPLICATIONS. THERE HAS BEEN A RAPID INCREASE IN THE INCIDENCE OF DIABETES AS WELL THE ASSOCIATED VASCULAR COMPLICATIONS. BOTH GENETIC AND ENVIRONMENTAL FACTORS HAVE BEEN IMPLICATED IN THESE PATHOLOGIES. INCREASING EVIDENCE SUGGESTS THAT EPIGENETIC FACTORS PLAY A KEY ROLE IN THE COMPLEX INTERPLAY BETWEEN GENES AND THE ENVIRONMENT. ACTIONS OF MAJOR PATHOLOGICAL MEDIATORS OF DIABETES AND ITS COMPLICATIONS SUCH AS HYPERGLYCAEMIA, OXIDANT STRESS, AND INFLAMMATORY FACTORS CAN LEAD TO DYSREGULATED EPIGENETIC MECHANISMS THAT AFFECT CHROMATIN STRUCTURE AND GENE EXPRESSION. FURTHERMORE, PERSISTENCE OF THIS ALTERED STATE OF THE EPIGENOME MAY BE THE UNDERLYING MECHANISM CONTRIBUTING TO A 'METABOLIC MEMORY' THAT RESULTS IN CHRONIC INFLAMMATION AND VASCULAR DYSFUNCTION IN DIABETES EVEN AFTER ACHIEVING GLYCAEMIC CONTROL. FURTHER EXAMINATION OF EPIGENETIC MECHANISMS BY ALSO TAKING ADVANTAGE OF RECENTLY DEVELOPED NEXT-GENERATION SEQUENCING TECHNOLOGIES CAN PROVIDE NOVEL INSIGHTS INTO THE PATHOLOGY OF DIABETES AND ITS COMPLICATIONS AND LEAD TO THE DISCOVERY OF MUCH NEEDED NEW DRUG TARGETS FOR THESE DISEASES. IN THIS REVIEW, WE HIGHLIGHT THE ROLE OF EPIGENETICS IN DIABETES AND ITS VASCULAR COMPLICATIONS, AND RECENT TECHNOLOGICAL ADVANCES THAT HAVE SIGNIFICANTLY ACCELERATED THE FIELD. 2011