1 2184 116 EPIGENETIC MECHANISMS THAT UNDERPIN METABOLIC AND CARDIOVASCULAR DISEASES. CELLULAR COMMITMENT TO A SPECIFIC LINEAGE IS CONTROLLED BY DIFFERENTIAL SILENCING OF GENES, WHICH IN TURN DEPENDS ON EPIGENETIC PROCESSES SUCH AS DNA METHYLATION AND HISTONE MODIFICATION. DURING EARLY EMBRYOGENESIS, THE MAMMALIAN GENOME IS 'WIPED CLEAN' OF MOST EPIGENETIC MODIFICATIONS, WHICH ARE PROGRESSIVELY RE-ESTABLISHED DURING EMBRYONIC DEVELOPMENT. THUS, THE EPIGENOME OF EACH MATURE CELLULAR LINEAGE CARRIES THE RECORD OF ITS DEVELOPMENTAL HISTORY. THE SUBSEQUENT TRAJECTORY AND PATTERN OF DEVELOPMENT ARE ALSO RESPONSIVE TO ENVIRONMENTAL INFLUENCES, AND SUCH PLASTICITY IS LIKELY TO HAVE AN EPIGENETIC BASIS. EPIGENETIC MARKS MAY BE TRANSMITTED ACROSS GENERATIONS, EITHER DIRECTLY BY PERSISTING THROUGH MEIOSIS OR INDIRECTLY THROUGH REPLICATION IN THE NEXT GENERATION OF THE CONDITIONS IN WHICH THE EPIGENETIC CHANGE OCCURRED. DEVELOPMENTAL PLASTICITY EVOLVED TO MATCH AN ORGANISM TO ITS ENVIRONMENT, AND A MISMATCH BETWEEN THE PHENOTYPIC OUTCOME OF ADAPTIVE PLASTICITY AND THE CURRENT ENVIRONMENT INCREASES THE RISK OF METABOLIC AND CARDIOVASCULAR DISEASE. THESE CONSIDERATIONS POINT TO EPIGENETIC PROCESSES AS A KEY MECHANISM THAT UNDERPINS THE DEVELOPMENTAL ORIGINS OF CHRONIC NONCOMMUNICABLE DISEASE. HERE, WE REVIEW THE EVIDENCE THAT ENVIRONMENTAL INFLUENCES DURING MAMMALIAN DEVELOPMENT LEAD TO STABLE CHANGES IN THE EPIGENOME THAT ALTER THE INDIVIDUAL'S SUSCEPTIBILITY TO CHRONIC METABOLIC AND CARDIOVASCULAR DISEASE, AND DISCUSS THE CLINICAL IMPLICATIONS. 2009 2 4126 45 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 3 6063 36 THE DEVELOPMENTAL ENVIRONMENT, EPIGENETIC BIOMARKERS AND LONG-TERM HEALTH. EVIDENCE FROM BOTH HUMAN AND ANIMAL STUDIES HAS SHOWN THAT THE PRENATAL AND EARLY POSTNATAL ENVIRONMENTS INFLUENCE SUSCEPTIBILITY TO CHRONIC DISEASE IN LATER LIFE AND SUGGESTS THAT EPIGENETIC PROCESSES ARE AN IMPORTANT MECHANISM BY WHICH THE ENVIRONMENT ALTERS LONG-TERM DISEASE RISK. EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND NON-CODING RNAS, PLAY A CENTRAL ROLE IN REGULATING GENE EXPRESSION. THE EPIGENOME IS HIGHLY SENSITIVE TO ENVIRONMENTAL FACTORS IN EARLY LIFE, SUCH AS NUTRITION, STRESS, ENDOCRINE DISRUPTION AND POLLUTION, AND CHANGES IN THE EPIGENOME CAN INDUCE LONG-TERM CHANGES IN GENE EXPRESSION AND PHENOTYPE. IN THIS REVIEW WE FOCUS ON HOW THE EARLY LIFE NUTRITIONAL ENVIRONMENT CAN ALTER THE EPIGENOME LEADING TO AN ALTERED SUSCEPTIBILITY TO DISEASE IN LATER LIFE. 2015 4 2007 36 EPIGENETIC BASIS FOR FETAL ORIGINS OF AGE-RELATED DISEASE. THE CURRENT CONCEPT OF FETAL ORIGINS OF ADULT DISEASES DESCRIBES IN UTERO PROGRAMMING, OR ADAPTATION TO A SPECTRUM OF ADVERSE ENVIRONMENTAL CONDITIONS THAT ULTIMATELY LEADS TO INCREASED SUSCEPTIBILITY TO AGE-RELATED DISEASES (E.G., TYPE 2 DIABETES AND CARDIOVASCULAR DISEASE) LATER IN LIFE. ALTHOUGH THE PRECISE MECHANISM OF THIS BIOLOGICAL MEMORY REMAINS UNCLEAR, MOUNTING EVIDENCE SUGGESTS AN EPIGENETIC BASIS. THE INCREASED SUSCEPTIBILITY TO CHRONIC DISEASE AND INVOLVEMENT OF MULTIPLE ORGAN SYSTEMS THAT IS OBSERVED IS ANALOGOUS TO THE DECLINE IN RESISTANCE TO DISEASE THAT IS TYPICAL OF NORMAL AGING. ALTHOUGH THE CUMULATIVE ENVIRONMENT OVER THE COURSE OF A LIFETIME CAN INDUCE INCREASING EPIGENETIC DYSREGULATION, WE PROPOSE THAT ADVERSE EVENTS THAT OCCUR DURING EARLY DEVELOPMENT CAN INDUCE SIGNIFICANT ADDITIONAL DYSREGULATION OF THE EPIGENOME. HERE, WE DESCRIBE THE CURRENT EVIDENCE FOR FETAL ORIGINS OF ADULT DISEASE AND THE ASSOCIATED ROLE OF EPIGENETIC DYSREGULATION. IN ADDITION, WE PRESENT A NEW PERSPECTIVE ON THE INDUCTION OF EPIGENETIC ALTERATIONS IN UTERO, WHICH SUBSEQUENTLY LEAD TO AN AGING PHENOTYPE MARKED BY INCREASED SUSCEPTIBILITY TO AGE-RELATED DISEASES. 2010 5 5376 44 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 6 6812 33 [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 7 6378 37 THE ROLE OF NUTRITION ON EPIGENETIC MODIFICATIONS AND THEIR IMPLICATIONS ON HEALTH. NUTRITION PLAYS A KEY ROLE IN MANY ASPECTS OF HEALTH AND DIETARY IMBALANCES ARE MAJOR DETERMINANTS OF CHRONIC DISEASES INCLUDING CARDIOVASCULAR DISEASE, OBESITY, DIABETES AND CANCER. ADEQUATE NUTRITION IS PARTICULARLY ESSENTIAL DURING CRITICAL PERIODS IN EARLY LIFE (BOTH PRE- AND POSTNATAL). IN THIS REGARD, THERE IS EXTENSIVE EPIDEMIOLOGIC AND EXPERIMENTAL DATA SHOWING THAT EARLY SUB-OPTIMAL NUTRITION CAN HAVE HEALTH CONSEQUENCES SEVERAL DECADES LATER. THE HYPOTHESIS THAT EPIGENETIC MECHANISMS MAY LINK SUCH NUTRITIONAL IMBALANCES WITH ALTERED DISEASE RISK HAS BEEN GAINING ACCEPTANCE OVER RECENT YEARS. EPIGENETICS CAN BE DEFINED AS THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION THAT DO NOT INVOLVE ALTERATIONS IN THE DNA SEQUENCE. EPIGENETIC MARKS INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS AND A VARIETY OF NON-CODING RNAS. STRIKINGLY, THEY ARE PLASTIC AND RESPOND TO ENVIRONMENTAL SIGNALS, INCLUDING DIET. HERE WE WILL REVIEW HOW DIETARY FACTORS MODULATE THE ESTABLISHMENT AND MAINTENANCE OF EPIGENETIC MARKS, THEREBY INFLUENCING GENE EXPRESSION AND, HENCE, DISEASE RISK AND HEALTH. 2012 8 2562 34 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 9 6251 42 THE MICROBIOLOGICAL MEMORY, AN EPIGENETIC REGULATOR GOVERNING THE BALANCE BETWEEN GOOD HEALTH AND METABOLIC DISORDERS. IF THE TRANSMISSION OF BIOLOGICAL INFORMATION FROM ONE GENERATION TO THE NEXT IS BASED ON DNA, MOST HERITABLE PHENOTYPIC TRAITS SUCH AS CHRONIC METABOLIC DISEASES, ARE NOT LINKED TO GENETIC VARIATION IN DNA SEQUENCES. NON-GENETIC HERITABILITY MIGHT HAVE SEVERAL CAUSES INCLUDING EPIGENETIC, PARENTAL EFFECT, ADAPTIVE SOCIAL LEARNING, AND INFLUENCE OF THE ECOLOGICAL ENVIRONMENT. DISTINGUISHING AMONG THESE CAUSES IS CRUCIAL TO RESOLVE MAJOR PHENOTYPIC ENIGMAS. STRONG EVIDENCE INDICATES THAT CHANGES IN DNA EXPRESSION THROUGH VARIOUS EPIGENETIC MECHANISMS CAN BE LINKED TO PARENT-OFFSPRING RESEMBLANCE IN TERMS OF SENSITIVITY TO METABOLIC DISEASES. AMONG NON-GENETIC HERITABLE TRAITS, EARLY NUTRITION COULD ACCOUNT FOR A LONG TERM DEVIANT PROGRAMMING OF GENES EXPRESSION RESPONSIBLE FOR METABOLIC DISEASES IN ADULTHOOD. NUTRITION COULD SHAPE AN INADEQUATE GUT MICROBIOTA (DYSBIOSIS), TRIGGERING EPIGENETIC DEREGULATION OF TRANSCRIPTION WHICH CAN BE OBSERVED IN CHRONIC METABOLIC DISEASES. WE REVIEW HEREIN THE EVIDENCE THAT DYSBIOSIS MIGHT BE A MAJOR CAUSE OF HERITABLE EPIGENETIC PATTERNS FOUND TO BE ASSOCIATED WITH METABOLIC DISEASES. BY TAKING INTO ACCOUNT THE RECENT ADVANCES ON THE GUT MICROBIOME, WE HAVE AGGREGATED TOGETHER DIFFERENT OBSERVATIONS SUPPORTING THE HYPOTHESIS THAT THE GUT MICROBIOTA COULD PROMOTE THE MOLECULAR CROSSTALK BETWEEN BACTERIA AND SURROUNDING HOST CELLS WHICH CONTROLS THE PATHOLOGICAL EPIGENETIC SIGNATURE. WE INTRODUCE FOR THE FIRST TIME THE CONCEPT OF "MICROBIOLOGICAL MEMORY" AS THE MAIN REGULATOR OF THE EPIGENETIC SIGNATURES, THEREBY INDICATING THAT DIFFERENT CAUSES OF NON-GENETIC HERITABILITY CAN INTERACT IN COMPLEX PATHWAYS TO PRODUCE INHERITANCE. 2018 10 6844 33 [METABOLIC PROGRAMMING: THEORETICAL CONCEPTS AND EXPERIMENTAL EVIDENCE]. IT IS KNOWN THAT THE POOR NUTRITION DURING A FETAL DEVELOPMENT MAY CONTRIBUTE TO AN INCREASED RISK OF CHRONIC DISEASES IN ADULTHOOD. IN A MODERN LITERATURE, THIS PHENOMENON IS CALLED <>. IT IS ASSUMED THAT THE QUALITATIVE OR QUANTITATIVE DEFICIENCY OF CERTAIN NUTRITIONAL COMPONENTS DURING AN EARLY DEVELOPMENT MAY LEAD TO THE ADAPTATIONS THAT CONTRIBUTE TO IMPROVED SURVIVAL DURING THE PRENATAL AND EARLY POSTNATAL PERIODS OF AN ONTOGENESIS. HOWEVER, THE CONSEQUENCE OF SUCH ADAPTIVE CHANGES MAY ALSO BE THE DEVELOPMENT OF VARIOUS PATHOLOGICAL PROCESSES AT THE LATER STAGES OF LIFE. RECENT STUDIES HAVE SHOWN THAT ONE OF THE MAJOR MECHANISMS INVOLVED IN THESE ADAPTATIONS IS THE EPIGENETIC REGULATION OF A GENE ACTIVITY. IN THIS REVIEW, THE EXPERIMENTAL EVIDENCE IS PROVIDED THAT PROCESSES ARISING FROM A QUANTITATIVELY OR QUALITATIVELY RESTRICTED DIET DURING THE EARLY STAGES OF DEVELOPMENT PLAY AN IMPORTANT ROLE IN THE FURTHER LIFE AND CAN GREATLY INFLUENCE RISK OF VARIOUS AGE-RELATED DISEASES AND LIFE SPAN. 2013 11 4392 34 MODIFIABLE RISK FACTORS IN PERIODONTAL DISEASE: EPIGENETIC REGULATION OF GENE EXPRESSION IN THE INFLAMMATORY RESPONSE. EPIGENETICS AS A MODIFIABLE RISK FACTOR IN PERIODONTAL DISEASES HAS BEEN INVESTIGATED IN LIGHT OF THE CURRENT KNOWLEDGE OF HOW CHRONIC INFECTION AND INFLAMMATION CAN AFFECT GENE-SPECIFIC EPIGENETIC REPROGRAMMING IN PERIODONTAL TISSUES. EPIGENOMIC PROGRAMMING MIGHT BE PARTICULARLY SENSITIVE TO ENVIRONMENTAL INFLUENCES, AND A COMBINATION OF PHYSIOLOGICAL STRESSORS AND ENVIRONMENTAL EXPOSURES APPEARS TO AFFECT THE EPIGENOMIC PROGRAM ACQUIRED BY A CELL DURING DIFFERENTIATION AND THROUGHOUT THE CELLULAR LINEAGE LIFESPAN. VIRAL AND BACTERIAL INFECTIONS CAN ESTABLISH SEVERAL TYPES OF EPIGENETIC MODIFICATIONS, WHICH SOMETIMES ENGAGE IN A COMPLEX EPIGENETIC CROSSTALK ALSO REFLECTING IN THE ESTABLISHMENT AND PROGRESS OF PERIODONTAL DISEASES. THE INFLAMMATORY AND METABOLIC STATES OF THE PERIODONTAL TISSUES ARE DRIVEN BY THE INFECTIOUS STIMULI, AND THE MAGNITUDE OF THE CELLULAR AND MOLECULAR SIGNATURE RESPONSE IS FURTHER DICTATED BY THE HOST GENETIC AND EPIGENETIC TRAITS ASSOCIATED WITH VARIOUS SYSTEMIC EXPOSURES, INCLUDING SMOKING, OBESITY AND DIABETES/HYPERGLYCEMIA. THIS REVIEW DISCUSSES THE ADVANCES IN EPIGENETICS, FOCUSING ON THE ROLE OF DNA METHYLATION IN THE PATHOGENESIS OF PERIODONTAL DISEASE AND THE POTENTIAL OF EPIGENETIC THERAPY. 2014 12 2103 32 EPIGENETIC EPIDEMIOLOGY OF THE DEVELOPMENTAL ORIGINS HYPOTHESIS. EXTENSIVE HUMAN EPIDEMIOLOGIC AND ANIMAL MODEL DATA INDICATE THAT DURING CRITICAL PERIODS OF PRENATAL AND POSTNATAL MAMMALIAN DEVELOPMENT, NUTRITION AND OTHER ENVIRONMENTAL STIMULI INFLUENCE DEVELOPMENTAL PATHWAYS AND THEREBY INDUCE PERMANENT CHANGES IN METABOLISM AND CHRONIC DISEASE SUSCEPTIBILITY. THE BIOLOGIC MECHANISMS UNDERLYING THIS "DEVELOPMENTAL ORIGINS HYPOTHESIS" ARE POORLY UNDERSTOOD. THIS REVIEW FOCUSES ON THE LIKELY INVOLVEMENT OF EPIGENETIC MECHANISMS IN THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD). WE DESCRIBE PERMANENT EFFECTS OF TRANSIENT ENVIRONMENTAL INFLUENCES ON THE DEVELOPMENTAL ESTABLISHMENT OF EPIGENETIC GENE REGULATION AND EVIDENCE LINKING EPIGENETIC DYSREGULATION WITH HUMAN DISEASE. WE PROPOSE A DEFINITION OF "EPIGENETIC EPIDEMIOLOGY" AND DELINEATE HOW THIS EMERGING FIELD PROVIDES A BASIS FROM WHICH TO EXPLORE THE ROLE OF EPIGENETIC MECHANISMS IN DOHAD. WE SUGGEST STRATEGIES FOR FUTURE HUMAN EPIDEMIOLOGIC STUDIES TO IDENTIFY CAUSAL ASSOCIATIONS BETWEEN EARLY EXPOSURES, LONG-TERM CHANGES IN EPIGENETIC REGULATION, AND DISEASE, WHICH MAY ULTIMATELY ENABLE SPECIFIC EARLY-LIFE INTERVENTIONS TO IMPROVE HUMAN HEALTH. 2007 13 3848 33 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 14 3706 37 INFLUENCE OF GENETICS ON DISEASE SUSCEPTIBILITY AND PROGRESSION. FOR MANY CHRONIC DISEASES, THE INFLUENCE OF GENETICS IS COMPLEX AND PHENOTYPES DO NOT CONFORM TO SIMPLE MENDELIAN PATTERNS OF INHERITANCE. DISCUSSED HERE ARE TWO TYPES OF GENETIC INFLUENCES ON HEALTHY AGING. THE FIRST INVOLVES VARIATION IN THE GENE SEQUENCE ITSELF AND HOW THIS MAY INFLUENCE DISEASE SUSCEPTIBILITY, PROGRESSION, AND SEVERITY, INTERACTING WITH OTHER RECOGNIZED RISK FACTORS. THE SECOND INVOLVES EPIGENETIC REGULATORY MECHANISMS THAT MAY POTENTIALLY PROVIDE INSIGHT INTO HOW ENVIRONMENTAL INFLUENCES AFFECT THE EXPRESSED GENOME, THUS IMPROVING OUR UNDERSTANDING OF THE GENETIC MECHANISMS UNDERLYING MULTIFACTORIAL DISEASES. THE INTERLEUKIN-1 FAMILY OF CYTOKINES CAN BE USED TO ILLUSTRATE HOW GENETIC SEQUENCE VARIATION MAY AFFECT SUCH DISEASES. THIS CYTOKINE FAMILY PLAYS A KEY ROLE IN MEDIATING INFLAMMATION, WHICH IS NOW UNDERSTOOD TO BE A CENTRAL COMPONENT OF A GROWING NUMBER OF CHRONIC DISEASES. RECENT WORK HAS REVEALED MANY SEQUENCE VARIATIONS IN THE REGULATORY DNA OF GENES ENCODING IMPORTANT MEMBERS OF THE INTERLEUKIN-1 FAMILY, AND THESE VARIATIONS ARE ASSOCIATED WITH DIFFERENTIAL EFFECTS ON THE INFLAMMATORY RESPONSE. THE INTERACTIONS OF ENVIRONMENTAL FACTORS WITH BOTH DNA SEQUENCE VARIATIONS AND EPIGENETIC MODIFICATIONS ARE LIKELY TO DETERMINE THE PHENOTYPES OF MULTIFACTORIAL DISEASES OF AGING AS WELL AS THE PHENOTYPE OF HEALTHY AGING. 2007 15 3404 36 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 16 2049 23 EPIGENETIC CODE AND POTENTIAL EPIGENETIC-BASED THERAPIES AGAINST CHRONIC DISEASES IN DEVELOPMENTAL ORIGINS. ACCUMULATED FINDINGS HAVE DEMONSTRATED THAT THE EPIGENETIC CODE PROVIDES A POTENTIAL LINK BETWEEN PRENATAL STRESS AND CHANGES IN GENE EXPRESSION THAT COULD BE INVOLVED IN THE DEVELOPMENTAL PROGRAMMING OF VARIOUS CHRONIC DISEASES IN LATER LIFE. MEANWHILE, BASED ON THE FACT THAT EPIGENETIC MODIFICATIONS ARE REVERSIBLE AND CAN BE MANIPULATED, THIS PROVIDES A UNIQUE CHANCE TO DEVELOP MULTIPLE NOVEL EPIGENETIC-BASED THERAPEUTIC STRATEGIES AGAINST MANY CHRONIC DISEASES IN EARLY DEVELOPMENTAL PERIODS. THIS ARTICLE WILL GIVE A SHORT REVIEW OF RECENT FINDINGS OF PRENATAL INSULT-INDUCED EPIGENETIC CHANGES IN DEVELOPMENTAL ORIGINS OF SEVERAL CHRONIC DISEASES, AND WILL ATTEMPT TO PROVIDE AN OVERVIEW OF THE CURRENT EPIGENETIC-BASED STRATEGIES APPLIED IN THE EARLY PREVENTION, DIAGNOSIS AND POSSIBLE THERAPIES FOR HUMAN CHRONIC DISEASES. 2014 17 2346 38 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 18 6809 31 [EPIGENETICS IN INFLAMMATORY SYSTEMIC DISEASES]. IN ADDITION TO ANALYSIS OF THE GENETIC CODE, IN RECENT YEARS MORE AND MORE STUDIES HAVE CONCENTRATED ON CHANGES IN THE EPIGENETIC CODE. EPIGENETIC MECHANISMS DETERMINE WHICH GENES IN A CELL ARE TRANSCRIBED AND THUS FORM THE PHENOTYPE OF A CELL. THE EPIGENETIC CODE CAN BE CHANGED BY ENVIRONMENTAL INFLUENCES, WHICH ALLOWS CELLS TO ADAPT TO LONGSTANDING CHANGES IN THE ENVIRONMENT. THEREFORE, IT IS FEASIBLE TO ASSUME THAT EPIGENETIC CHANGES ARE THE MOLECULAR BASIS FOR LONG-TERM EFFECTS OF THE ENVIRONMENT ON DISEASE DEVELOPMENT. IN PARTICULAR IN TUMORS AND CHRONIC INFLAMMATORY DISEASES EPIGENETIC CHANGES WERE FOUND TO CORRELATE WITH DISEASE SEVERITY AND PROGRESSION. KNOWLEDGE ABOUT THESE EPIGENETIC CHANGES MIGHT HELP THAT EPIGENETIC MODIFICATIONS CAN BE USED IN THE FUTURE AS BIOMARKERS, PROGNOSTIC FACTORS AND THERAPEUTIC TARGETS. 2014 19 2282 38 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 20 6886 36 [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