1 2497 74 EPIGENETICS AND ENVIRONMENTAL LUNG DISEASE. GENE-ENVIRONMENT INTERACTIONS ARE THE INDISPUTABLE CAUSE OF MOST RESPIRATORY DISEASES. HOWEVER, WE STILL HAVE VERY LIMITED UNDERSTANDING OF THE MECHANISMS THAT GUIDE THESE INTERACTIONS. ALTHOUGH THE CONCEPTUAL APPROACHES TO ENVIRONMENTAL GENOMICS WERE ESTABLISHED SEVERAL DECADES AGO, THE TOOLS ARE ONLY NOW AVAILABLE TO BETTER DEFINE THE MECHANISMS THAT UNDERLIE THE INTERACTION BETWEEN THESE IMPORTANT ETIOLOGIC FEATURES OF LUNG DISEASE. EPIGENETIC MECHANISMS CAN MEDIATE THE EFFECT OF THE ENVIRONMENT ON THE HUMAN GENOME BY CONTROLLING THE TRANSCRIPTIONAL ACTIVITY OF SPECIFIC GENES, AT SPECIFIC POINTS IN TIME, IN SPECIFIC ORGANS. IN THIS ARTICLE, WE DEMONSTRATE THE POTENTIAL IMPORTANCE OF EPIGENETIC MECHANISMS IN THE DEVELOPMENT AND PROGRESSION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND ASTHMA. 2010 2 6199 34 THE IMPORTANCE OF EPIGENETICS IN THE DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IT IS GENERALLY ACCEPTED THAT GENETIC PREDISPOSITION PLAYS A ROLE IN COPD DEVELOPMENT IN SUSCEPTIBLE INDIVIDUALS. THEREFORE, MANY CANDIDATE GENES THAT COULD BE LINKED TO THE DEVELOPMENT OF DISEASE HAVE BEEN EXAMINED IN COPD. HOWEVER, INCONSISTENT RESULTS IN DIFFERENT STUDY POPULATIONS OFTEN LIMIT THIS APPROACH, SUGGESTING THAT NOT ONLY GENETICS, BUT ALSO OTHER FACTORS, MAY BE CONTRIBUTED TO THE SUSCEPTIBILITY TO COPD. EPIGENETIC MECHANISMS CAN AFFECT THE TRANSCRIPTIONAL ACTIVITY OF SPECIFIC GENES, AT DIFFERENT POINTS IN TIME, AND IN DIFFERENT ORGANS. MOREOVER, THESE MECHANISMS CAN HAVE AN EFFECT ON PEOPLE'S HEALTH. RECENTLY, THERE IS EMERGING EVIDENCE SUPPORTING A ROLE OF EPIGENETICS FOR THE REGULATION OF INFLAMMATORY GENES IN DISEASES SUCH AS ASTHMA AND COPD. MOREOVER, RECENT STUDIES SUGGEST THAT THE CURRENTLY USED TREATMENTS INCLUDING CORTICOSTEROIDS MAY WORK THROUGH EPIGENETIC MECHANISMS. EPIGENETIC REGULATION CAN BE REPROGRAMMED, POTENTIALLY AFFECTING THE RISK, AETIOLOGY AND TREATMENT OF VARIOUS DISEASE STATES. THE EPIGENETICALLY INFLUENCED PHENOTYPE COULD BE REVERSED WITH DEMETHYLATING OR DEACETYLATING AGENTS, CONSISTENT WITH EPIGENETIC PLASTICITY. THE POSTNATAL REVERSIBILITY OF THESE METHYLATION OR ACETYLATION EVENTS MAY THEREFORE PROVIDE GOOD OPPORTUNITIES FOR INTERVENTION. THE RECOGNITION OF THE ROLE OF GENETIC AND EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF COPD MAY IDENTIFY NOVEL TARGETS THAT HATCH NEW THERAPIES FOR PATIENTS WITH COPD. 2011 3 3028 18 GENETICS OF COMPLEX AIRWAY DISEASE. THE PAST 3 YEARS HAVE SEEN HIGHLY SIGNIFICANT GENETIC EFFECTS IDENTIFIED FOR A WIDE VARIETY OF COMMON COMPLEX DISEASES, INCLUDING THE AIRWAY DISORDERS OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IT APPEARS THAT ONLY A PORTION OF THE GENETICALLY MEDIATED SUSCEPTIBILITY TO COMPLEX DISEASES HAS BEEN IDENTIFIED, AND THERE IS MUCH LEFT TO BE DISCOVERED. THIS REVIEW BRIEFLY DESCRIBES THE RESULTS OF THE GENOME-WIDE ASSOCIATION STUDIES OF ASTHMA AND GIVES AN OVERVIEW OF THE PARALLEL AND INCREASINGLY LARGE-SCALE STUDIES THAT ARE TAKING PLACE WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE FUTURE IMPACT IS DISCUSSED OF TECHNOLOGICAL ADVANCES THAT ALLOW INCREASINGLY LARGE-SCALE GENE EXPRESSION STUDIES, NEXT-GENERATION SEQUENCING, AND GENOME-WIDE TESTING FOR EPIGENETIC EFFECTS. THE USE OF GENETIC TECHNOLOGY TO EXAMINE THE AIRWAY MICROBIOTA THAT INTERACT WITH THE MUCOSA IN HEALTH AND DISEASE IS DESCRIBED. 2011 4 6735 24 WHAT HAVE MECHANISTIC STUDIES TAUGHT US ABOUT CHILDHOOD ASTHMA? CHILDHOOD ASTHMA IS A CHRONIC HETEROGENEOUS SYNDROME CONSISTING OF DIFFERENT DISEASE ENTITIES OR PHENOTYPES. THE IMMUNOLOGIC AND CELLULAR PROCESSES THAT OCCUR DURING ASTHMA DEVELOPMENT ARE STILL NOT FULLY UNDERSTOOD BUT REPRESENT DISTINCT ENDOTYPES. MECHANISTIC STUDIES HAVE EXAMINED THE ROLE OF GENE EXPRESSION, PROTEIN LEVELS, AND CELL TYPES IN EARLY LIFE DEVELOPMENT AND THE MANIFESTATION OF ASTHMA, MANY UNDER THE INFLUENCE OF ENVIRONMENTAL STIMULI, WHICH CAN BE BOTH PROTECTIVE AND RISK FACTORS FOR ASTHMA. GENETIC VARIANTS CAN REGULATE GENE EXPRESSION, CONTROLLED PARTLY BY DIFFERENT EPIGENETIC MECHANISMS. IN ADDITION, ENVIRONMENTAL FACTORS, SUCH AS LIVING SPACE, NUTRITION, AND SMOKING, CAN CONTRIBUTE TO THESE MECHANISMS. ALL OF THESE FACTORS PRODUCE MODIFICATIONS IN GENE EXPRESSION THAT CAN ALTER THE DEVELOPMENT AND FUNCTION OF IMMUNE AND EPITHELIAL CELLS AND SUBSEQUENTLY DIFFERENT TRAJECTORIES OF CHILDHOOD ASTHMA. THESE EARLY CHANGES IN A PARTIALLY IMMATURE IMMUNE SYSTEM CAN HAVE DRAMATIC EFFECTS (E.G., CAUSING DYSREGULATION), WHICH IN TURN CONTRIBUTE TO DIFFERENT DISEASE ENDOTYPES AND MAY HELP TO EXPLAIN DIFFERENTIAL RESPONSIVENESS TO ASTHMA TREATMENT. IN THIS REVIEW, WE SUMMARIZE PUBLISHED STUDIES THAT HAVE AIMED TO UNCOVER DISTINCT MECHANISMS IN CHILDHOOD ASTHMA, CONSIDERING GENETICS, EPIGENETICS, AND ENVIRONMENT. MOREOVER, A DISCUSSION OF NEW, POWERFUL TOOLS FOR SINGLE-CELL IMMUNOLOGIC ASSAYS FOR PHENOTYPIC AND FUNCTIONAL ANALYSIS IS INCLUDED, WHICH PROMISE NEW MECHANISTIC INSIGHTS INTO CHILDHOOD ASTHMA DEVELOPMENT AND THERAPEUTIC AND PREVENTIVE STRATEGIES. 2023 5 3404 23 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 6 396 27 AN UPDATE ON EPIGENETICS AND CHILDHOOD RESPIRATORY DISEASES. EPIGENETIC MECHANISMS, DEFINED AS CHANGES IN PHENOTYPE OR GENE EXPRESSION CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE, HAVE BEEN PROPOSED TO CONSTITUTE A LINK BETWEEN GENETIC AND ENVIRONMENTAL FACTORS THAT AFFECT COMPLEX DISEASES. RECENT STUDIES SHOW THAT DNA METHYLATION, ONE OF THE KEY EPIGENETIC MECHANISMS, IS ALTERED IN CHILDREN EXPOSED TO AIR POLLUTANTS AND ENVIRONMENTAL TOBACCO SMOKE EARLY IN LIFE. SEVERAL CANDIDATE GENE STUDIES ON EPIGENETICS HAVE BEEN PUBLISHED TO DATE, BUT IT IS ONLY RECENTLY THAT GLOBAL METHYLATION ANALYSES HAVE BEEN PERFORMED FOR RESPIRATORY DISORDERS SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. HOWEVER, LARGE-SCALE STUDIES WITH ADEQUATE POWER ARE YET TO BE PRESENTED IN CHILDREN, AND IMPLICATIONS FOR CLINICAL USE REMAIN TO BE EVALUATED. IN THIS REVIEW, WE SUMMARIZE THE RECENT ADVANCES IN EPIGENETICS AND RESPIRATORY DISORDERS IN CHILDREN, WITH A MAIN FOCUS ON METHODOLOGICAL CHALLENGES AND ANALYSES RELATED TO PHENOTYPE AND EXPOSURE USING GLOBAL METHYLATION APPROACHES. 2014 7 2330 22 EPIGENETIC REGULATION OF IMMUNE FUNCTION IN ASTHMA. ASTHMA IS A COMMON COMPLEX RESPIRATORY DISEASE CHARACTERIZED BY CHRONIC AIRWAY INFLAMMATION AND PARTIALLY REVERSIBLE AIRFLOW OBSTRUCTION RESULTING FROM GENETIC AND ENVIRONMENTAL DETERMINANTS. BECAUSE EPIGENETIC MARKS INFLUENCE GENE EXPRESSION AND CAN BE MODIFIED BY BOTH ENVIRONMENTAL EXPOSURES AND GENETIC VARIATION, THEY ARE INCREASINGLY RECOGNIZED AS RELEVANT TO THE PATHOGENESIS OF ASTHMA AND MAY BE A KEY LINK BETWEEN ENVIRONMENTAL EXPOSURES AND ASTHMA SUSCEPTIBILITY. UNLIKE CHANGES TO DNA SEQUENCE, EPIGENETIC SIGNATURES ARE DYNAMIC AND REVERSIBLE, CREATING AN OPPORTUNITY FOR NOT ONLY THERAPEUTIC TARGETS BUT MAY SERVE AS BIOMARKERS TO FOLLOW DISEASE COURSE AND IDENTIFY MOLECULAR SUBTYPES IN HETEROGENEOUS DISEASES SUCH AS ASTHMA. IN THIS REVIEW, WE WILL EXAMINE THE RELATIONSHIP BETWEEN ASTHMA AND 3 KEY EPIGENETIC PROCESSES THAT MODIFY GENE EXPRESSION: DNA METHYLATION, MODIFICATION OF HISTONE TAILS, AND NONCODING RNAS. IN ADDITION TO PRESENTING A COMPREHENSIVE ASSESSMENT OF THE EXISTING EPIGENETIC STUDIES FOCUSING ON IMMUNE REGULATION IN ASTHMA, WE WILL DISCUSS FUTURE DIRECTIONS FOR EPIGENETIC INVESTIGATION IN ALLERGIC AIRWAY DISEASE. 2022 8 5552 23 ROLE OF EPIGENETICS IN THE PATHOGENESIS OF ASTHMA. ASTHMA IS A COMPLEX, HETEROGENEOUS AND CHRONIC AIRWAY INFLAMMATORY DISEASE WITH DIFFERENT CLINICAL PHENOTYPES CAUSED BY DIVERSE TRIGGERS AND PATHOPHYSIOLOGICAL MECHANISMS. ASTHMA HERITABILITY HAS BEEN ESTABLISHED IN MANY GENETIC STUDIES BUT IT IS EVIDENT THAT ONLY GENETIC ELEMENTS ARE NOT RESPONSIBLE FOR THE DEVELOPMENT OF ASTHMA. INCREASING RATE OF ASTHMA INCIDENCE DURING PAST DECADES HAS IMPLICATED THE ROLE OF EPIGENETICS IN DEVELOPMENT OF ASTHMA. ENVIRONMENTAL FACTORS PERFORM AS INITIATOR SIGNALS THROUGH EPIGENETIC MECHANISMS. THREE EPIGENETIC MECHANISMS HAVE BEEN IDENTIFIED, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND SMALL NONCODING RNAS. THESE MECHANISMS REGULATE THE IMMUNE RESPONSES AND INFLAMMATORY GENES EXPRESSION IN ASTHMA AND ALLERGY. THIS REVIEW EXPLAINS THE ROLE OF EPIGENETIC MODIFICATIONS IN CONTROLLING TH2 RESPONSE AND IGE PRODUCTION IN ASTHMA AND ALSO BRIEFLY OVERVIEWS THE ROLE OF ENVIRONMENTAL FACTORS SUCH AS POLLUTIONS, ALLERGENS, PRENATAL EXPOSURES AND DIET IN DEVELOPING ASTHMA. RECOGNIZING ENVIRONMENTAL RISK FACTORS AND THEIR EFFECTS ON EPIGENETIC MECHANISMS WOULD BE OF GREAT INTEREST FOR PROGNOSTIC AND PREVENTIVE ASPECT IN TREATMENT OF ASTHMA. 2017 9 2984 23 GENETIC DETERMINANTS OF POOR RESPONSE TO TREATMENT IN SEVERE ASTHMA. SEVERE ASTHMA IS A MULTIFACTORIAL DISORDER WITH MARKED PHENOTYPIC HETEROGENEITY AND COMPLEX INTERACTIONS BETWEEN GENETICS AND ENVIRONMENTAL RISK FACTORS, WHICH COULD, AT LEAST IN PART, EXPLAIN WHY DURING STANDARD PHARMACOLOGIC TREATMENT, MANY PATIENTS REMAIN POORLY CONTROLLED AND AT AN INCREASED RISK OF AIRWAY REMODELING AND DISEASE PROGRESSION. THE CONCEPT OF "PRECISION MEDICINE" TO BETTER SUIT INDIVIDUAL UNIQUE NEEDS IS AN EMERGING TREND IN THE MANAGEMENT OF CHRONIC RESPIRATORY DISEASES. OVER THE PAST FEW YEARS, GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE REVEALED NOVEL PHARMACOGENETIC VARIANTS RELATED TO RESPONSES TO INHALED CORTICOSTEROIDS AND THE CLINICAL EFFICACY OF BRONCHODILATORS. OPTIMAL CLINICAL RESPONSE TO TREATMENT MAY VARY BETWEEN RACIAL/ETHNIC GROUPS OR INDIVIDUALS DUE TO GENETIC DIFFERENCES. IT IS ALSO PLAUSIBLE TO ASSUME THAT EPIGENETIC FACTORS PLAY A KEY ROLE IN THE MODULATION OF GENE EXPRESSION PATTERNS AND INFLAMMATORY CYTOKINES. REMARKABLY, SPECIFIC GENETIC VARIANTS RELATED TO TREATMENT EFFECTIVENESS MAY INDICATE PROMISING PATHWAYS FOR NOVEL THERAPIES IN SEVERE ASTHMA. IN THIS REVIEW, WE PROVIDE A CONCISE UPDATE OF GENETIC DETERMINANTS OF POOR RESPONSE TO TREATMENT IN SEVERE ASTHMA AND FUTURE DIRECTIONS IN THE FIELD. 2021 10 2333 23 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 11 5376 27 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 12 6809 23 [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 13 3706 25 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 14 2154 27 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 15 738 23 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 16 6288 29 THE POTENTIAL ROLE OF EPIGENETIC MODIFICATIONS ON DIFFERENT FACETS IN THE PERIODONTAL PATHOGENESIS. PERIODONTITIS IS A CHRONIC INFLAMMATORY DISEASE THAT AFFECTS THE SUPPORTING STRUCTURES OF TEETH. IN THE LITERATURE, THE ASSOCIATION BETWEEN THE PATHOGENICITY OF BACTERIA AND ENVIRONMENTAL FACTORS IN THIS REGARD HAVE BEEN EXTENSIVELY EXAMINED. IN THE PRESENT STUDY, WE WILL SHED LIGHT ON THE POTENTIAL ROLE THAT EPIGENETIC CHANGE CAN PLAY ON DIFFERENT FACETS OF ITS PROCESS, MORE PARTICULARLY THE MODIFICATIONS CONCERNING THE GENES INVOLVED IN INFLAMMATION, DEFENSE, AND IMMUNE SYSTEMS. SINCE THE 1960S, THE ROLE OF GENETIC VARIANTS IN THE ONSET AND SEVERITY OF PERIODONTAL DISEASE HAS BEEN WIDELY DEMONSTRATED. THESE MAKE SOME PEOPLE MORE SUSCEPTIBLE TO DEVELOPING IT THAN OTHERS. IT HAS BEEN DOCUMENTED THAT THE WIDE VARIATION IN ITS FREQUENCY FOR VARIOUS RACIAL AND ETHNIC POPULATIONS IS DUE PRIMARILY TO THE COMPLEX INTERPLAY AMONG GENETIC FACTORS WITH THOSE AFFECTING THE ENVIRONMENT AND THE DEMOGRAPHY. IN MOLECULAR BIOLOGY, EPIGENETIC MODIFICATIONS ARE DEFINED AS ANY CHANGE IN THE PROMOTER FOR THE CPG ISLANDS, IN THE STRUCTURE OF THE HISTONE PROTEIN, AS WELL AS POST-TRANSLATIONAL REGULATION BY MICRORNAS (MIRNAS), BEING KNOWN TO CONTRIBUTE TO THE ALTERATION IN GENE EXPRESSION FOR COMPLEX MULTIFACTORIAL DISEASES SUCH AS PERIODONTITIS. THE KEY ROLE OF EPIGENETIC MODIFICATION IS TO UNDERSTAND THE MECHANISM INVOLVED IN THE GENE-ENVIRONMENT INTERACTION, AND THE DEVELOPMENT OF PERIODONTITIS IS NOW THE SUBJECT OF MORE AND MORE STUDIES THAT ATTEMPT TO IDENTIFY WHICH FACTORS ARE STIMULATING IT, BUT ALSO AFFECT THE REDUCED RESPONSE TO THERAPY. 2023 17 2492 23 EPIGENETICS AND CHILDHOOD ASTHMA: CURRENT EVIDENCE AND FUTURE RESEARCH DIRECTIONS. ASTHMA IS THE MOST COMMON CHRONIC DISEASE OF CHILDHOOD, AFFECTING ONE IN EIGHT CHILDREN IN THE USA AND WORLDWIDE. IT IS A COMPLEX DISEASE, INFLUENCED BY BOTH ENVIRONMENTAL EXPOSURES AND GENETIC FACTORS. ALTHOUGH EPIGENETIC MODIFICATIONS (DNA METHYLATION, HISTONE MODIFICATION AND MIRNA) CAN AFFECT TRANSCRIPTIONAL ACTIVITY IN MULTIPLE GENETIC PATHWAYS RELEVANT FOR ASTHMA DEVELOPMENT, VERY LIMITED WORK HAS BEEN CARRIED OUT SO FAR TO EXAMINE THE ROLE OF EPIGENETIC VARIATIONS ON ASTHMA DEVELOPMENT AND MANAGEMENT. THIS REVIEW PROVIDES A BRIEF OVERVIEW OF EPIGENETIC MODIFICATIONS, SUMMARIZES RECENT FINDINGS, AND DISCUSSES SOME OF THE MAJOR METHODOLOGICAL CONCERNS THAT ARE RELEVANT FOR ASTHMA EPIGENETICS. 2012 18 2570 20 EPIGENETICS OF CHRONIC INFLAMMATORY DISEASES. CHRONIC, NONCOMMUNICABLE, AND INFLAMMATION-ASSOCIATED DISEASES REMAIN THE LARGEST CAUSE OF MORBIDITY AND MORTALITY GLOBALLY AND WITHIN THE UNITED STATES. THIS IS MAINLY DUE TO OUR LIMITED UNDERSTANDING OF THE MOLECULAR MECHANISMS THAT UNDERLIE THESE COMPLEX PATHOLOGIES. THE AVAILABLE EVIDENCE INDICATES THAT STUDIES OF EPIGENETICS (TRADITIONALLY DEFINED AS THE HERITABLE CHANGES TO GENE EXPRESSION THAT ARE INDEPENDENT OF CHANGES TO DNA) ARE SIGNIFICANTLY ADVANCING OUR KNOWLEDGE OF THESE INFLAMMATORY CONDITIONS. THIS REVIEW WILL FOCUS ON EPIGENETIC STUDIES OF THREE DISEASES, THAT ARE AMONG THE MOST BURDENSOME GLOBALLY: CARDIOVASCULAR DISEASE, THE NUMBER ONE CAUSE OF DEATHS WORLDWIDE, TYPE 2 DIABETES AND, ALZHEIMER'S DISEASE. THE CURRENT STATUS OF EPIGENETIC RESEARCH, INCLUDING THE ABILITY TO PREDICT DISEASE RISK, AND KEY PATHOPHYSIOLOGICAL DEFECTS ARE DISCUSSED. THE SIGNIFICANCE OF DEFINING THE CONTRIBUTION OF EPIGENETIC DEFECTS TO NONRESOLVING INFLAMMATION AND AGING, EACH ASSOCIATED WITH THESE DISEASES, IS HIGHLIGHTED, AS THESE ARE LIKELY TO PROVIDE NEW INSIGHTS INTO INFLAMMATORY DISEASE PATHOGENESIS. 2019 19 2531 21 EPIGENETICS IN ASTHMA. PURPOSE OF REVIEW: ASTHMA IS ONE OF THE MOST COMMON CHRONIC RESPIRATORY DISEASES LINKED WITH INCREASED MORBIDITY AND HEALTHCARE UTILIZATION. THE UNDERLYING PATHOPHYSIOLOGICAL PROCESSES AND CAUSAL RELATIONSHIPS OF ASTHMA WITH EPIGENETIC MECHANISMS ARE PARTIALLY UNDERSTOOD. HERE WE REVIEW HUMAN STUDIES OF EPIGENETIC MECHANISMS IN ASTHMA, WITH A SPECIAL FOCUS ON DNA METHYLATION. RECENT FINDINGS: EPIGENETIC STUDIES OF CHILDHOOD ASTHMA HAVE IDENTIFIED SPECIFIC METHYLATION SIGNATURES ASSOCIATED WITH ALLERGIC INFLAMMATION IN THE AIRWAY AND IMMUNE CELLS, DEMONSTRATING A REGULATORY ROLE FOR METHYLATION IN ASTHMA PATHOGENESIS. DESPITE THESE NOVEL FINDINGS, ADDITIONAL RESEARCH IN THE ROLE OF EPIGENETIC MECHANISMS UNDERLYING ASTHMA ENDOTYPES IS NEEDED. SIMILARLY, STUDIES OF HISTONE MODIFICATIONS ARE ALSO LACKING IN ASTHMA. FUTURE STUDIES OF EPIGENETIC MECHANISMS IN ASTHMA WILL BENEFIT FROM DATA INTEGRATION IN WELL PHENOTYPED COHORTS. THIS REVIEW PROVIDES AN OVERVIEW OF THE CURRENT LITERATURE ON EPIGENETIC STUDIES IN HUMAN ASTHMA, WITH SPECIAL EMPHASIS ON METHYLATION AND CHILDHOOD ASTHMA. 2019 20 2651 26 EPIGENOMICS AND TRANSCRIPTOMICS IN THE PREDICTION AND DIAGNOSIS OF CHILDHOOD ASTHMA: ARE WE THERE YET? ASTHMA IS THE MOST COMMON NON-COMMUNICABLE CHRONIC DISEASE OF CHILDHOOD. DESPITE ITS HIGH PREVALENCE, TO DATE WE LACK METHODS THAT ARE BOTH EFFICIENT AND ACCURATE IN DIAGNOSING ASTHMA. MOST TRADITIONAL APPROACHES HAVE BEEN BASED ON GARNERING CLINICAL EVIDENCE, SUCH AS RISK FACTORS AND EXPOSURES. GIVEN THE HIGH HERITABILITY OF ASTHMA, MORE RECENT APPROACHES HAVE LOOKED AT GENETIC POLYMORPHISMS AS POTENTIAL "RISK FACTORS." HOWEVER, GENETIC VARIANTS EXPLAIN ONLY A SMALL PROPORTION OF ASTHMA RISK, AND HAVE BEEN LESS THAN OPTIMAL AT PREDICTING RISK FOR INDIVIDUAL SUBJECTS. EPIGENOMIC STUDIES OFFER SIGNIFICANT ADVANTAGES OVER PREVIOUS APPROACHES. EPIGENETIC REGULATION IS HIGHLY TISSUE-SPECIFIC, AND CAN INDUCE BOTH SHORT- AND LONG-TERM CHANGES IN GENE EXPRESSION. SUCH CHANGES CAN START IN UTERO, CAN VARY THROUGHOUT THE LIFE SPAN, AND IN SOME INSTANCES CAN BE PASSED ON FROM ONE GENERATION TO ANOTHER. MOST IMPORTANTLY, THE EPIGENOME CAN BE MODIFIED BY ENVIRONMENTAL FACTORS AND EXPOSURES, AND THUS EPIGENETIC AND TRANSCRIPTOMIC PROFILING MAY YIELD THE MOST ACCURATE RISK ESTIMATES FOR A GIVEN PATIENT BY INCORPORATING ENVIRONMENTAL (AND TREATMENT) EFFECTS THROUGHOUT THE LIFESPAN. HERE WE WILL REVIEW THE MOST RECENT ADVANCES IN THE USE OF EPIGENETIC AND TRANSCRIPTOMIC ANALYSIS FOR THE EARLY DIAGNOSIS OF ASTHMA AND ATOPY, AS WELL AS CHALLENGES AND FUTURE DIRECTIONS IN THE FIELD AS IT MOVES FORWARD. WE WILL PARTICULARLY FOCUS ON DNA METHYLATION, THE MOST STUDIED MECHANISM OF EPIGENETIC REGULATION. 2019