1 4826 124 OF PLEIOTROPY AND TRAJECTORIES: DOES THE TGF-BETA PATHWAY LINK CHILDHOOD ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE? THE STUDY OF DEVELOPMENTAL TRAJECTORIES IS WHERE EPIGENETICS TRULY SHINES. THE "EPI" IN EPIGENETICS CAPTURES THE FACT THAT ALTHOUGH EPIGENETIC PROCESSES ALSO PRESIDE OVER THE MAINTENANCE AND TERMINATION OF GENE EXPRESSION, THE UNFOLDING AND REMODELING OF CHROMATIN ARCHITECTURE ARE ESPECIALLY CRITICAL TO PREPARE GENES FOR REGULATED TRANSCRIPTION. THESE PROPERTIES IMPLY BEING ON A PATH, A TRAJECTORY TO EVENTS THAT WILL OCCUR LATER THANKS TO EPIGENETIC PROGRAMMING. THUS EPIGENETICS IS ABOUT TIMED AND TIMELY EVENTS. IN THIS ARTICLE WE DISCUSS EPIGENETIC AND GENETIC EVIDENCE FROM SEVERAL INDEPENDENT STUDIES OF ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND LUNG FUNCTION, WHICH CONVERGE TO HIGHLIGHT A POTENTIAL ROLE OF THE TGF-BETA GENE PATHWAY IN THESE PROCESSES. THESE RESULTS RAISE THE POSSIBILITY THAT AT LEAST IN A SUBSET OF SUBJECTS, THESE CONDITIONS MIGHT BE FUNCTIONALLY CONNECTED IN WAYS THAT NEED TO BE FURTHER DEFINED BUT THAT LIKELY REFLECT THE UNIQUELY PLEIOTROPIC NATURE OF TGF-BETA PATHWAY GENES, PARTICULARLY THEIR ABILITY TO CONTROL BOTH LUNG DEVELOPMENT AND IMMUNE RESPONSES ESSENTIAL FOR REGULATION AND INFLAMMATION. FURTHER CHARACTERIZATION OF THIS PATHWAY IN LONGITUDINALLY PHENOTYPED POPULATIONS MIGHT UNMASK NOVEL TRAJECTORIES TO LUNG DISEASE THAT BEGIN IN UTERO AND UNFOLD INTO OLD AGE. 2018 2 6199 38 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 2497 26 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 4 2279 34 EPIGENETIC REGULATION IN ALLERGIC DISEASES AND RELATED STUDIES. ASTHMA, A CHRONIC INFLAMMATORY DISORDER OF THE AIRWAY, HAS FEATURES OF BOTH HERITABILITY AS WELL AS ENVIRONMENTAL INFLUENCES WHICH CAN BE INTRODUCED IN UTERO EXPOSURES AND MODIFIED THROUGH AGING, AND THE FEATURES MAY ATTRIBUTE TO EPIGENETIC REGULATION. EPIGENETIC REGULATION EXPLAINS THE ASSOCIATION BETWEEN EARLY PRENATAL MATERNAL SMOKING AND LATER ASTHMA-RELATED OUTCOMES. EPIGENETIC MARKS (DNA METHYLATION, MODIFICATIONS OF HISTONE TAILS OR NONCODING RNAS) WORK WITH OTHER COMPONENTS OF THE CELLULAR REGULATORY MACHINERY TO CONTROL THE LEVELS OF EXPRESSED GENES, AND SEVERAL ALLERGY- AND ASTHMA-RELATED GENES HAVE BEEN FOUND TO BE SUSCEPTIBLE TO EPIGENETIC REGULATION, INCLUDING GENES IMPORTANT TO T-EFFECTOR PATHWAYS (IFN-GAMMA, INTERLEUKIN [IL] 4, IL-13, IL-17) AND T-REGULATORY PATHWAYS (FOXP3). THEREFORE, THE MECHANISM BY WHICH EPIGENETIC REGULATION CONTRIBUTES TO ALLERGIC DISEASES IS A CRITICAL ISSUE. IN THE PAST MOST PUBLISHED EXPERIMENTAL WORK, WITH FEW EXCEPTIONS, HAS ONLY COMPRISED SMALL OBSERVATIONAL STUDIES AND MODELS IN CELL SYSTEMS AND ANIMALS. HOWEVER, VERY RECENTLY EXCITING AND ELEGANT EXPERIMENTAL STUDIES AND NOVEL TRANSLATIONAL RESEARCH WORKS WERE PUBLISHED WITH NEW AND ADVANCED TECHNOLOGIES INVESTIGATING EPIGENETIC MARK ON A GENOMIC SCALE AND COMPREHENSIVE APPROACHES TO DATA ANALYSIS. INTERESTINGLY, A POTENTIAL LINK BETWEEN EXPOSURE TO ENVIRONMENTAL POLLUTANTS AND THE OCCURRENCE OF ALLERGIC DISEASES IS REVEALED RECENTLY, PARTICULAR IN DEVELOPED AND INDUSTRIALIZED COUNTRIES, AND ENDOCRINE DISRUPTING CHEMICALS (EDCS) AS ENVIRONMENTAL HORMONE MAY PLAY A KEY ROLE. THIS REVIEW ADDRESSES THE IMPORTANT QUESTION OF HOW EDCS (NONYLPHENOL, 4 OCTYLPHENOL, AND PHTHALATES) INFLUENCES ON ASTHMA-RELATED GENE EXPRESSION VIA EPIGENETIC REGULATION IN IMMUNE CELLS, AND HOW ANTI-ASTHMATIC AGENTS PROHIBIT EXPRESSION OF INFLAMMATORY GENES VIA EPIGENETIC MODIFICATION. THE DISCOVERY AND VALIDATION OF EPIGENETIC BIOMARKERS LINKING EXPOSURE TO ALLERGIC DISEASES MIGHT LEAD TO BETTER EPIGENOTYPING OF RISK, PROGNOSIS, TREATMENT PREDICTION, AND DEVELOPMENT OF NOVEL THERAPIES. 2014 5 6809 28 [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 6 2059 30 EPIGENETIC CONTROL OF GENE EXPRESSION IN THE LUNG. EPIGENETICS IS TRADITIONALLY DEFINED AS THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE. THERE ARE THREE MAIN CLASSES OF EPIGENETIC MARKS--DNA METHYLATION, MODIFICATIONS OF HISTONE TAILS, AND NONCODING RNAS--EACH OF WHICH MAY BE INFLUENCED BY THE ENVIRONMENT, DIET, DISEASES, AND AGEING. IMPORTANTLY, EPIGENETIC MARKS HAVE BEEN SHOWN TO INFLUENCE IMMUNE CELL MATURATION AND ARE ASSOCIATED WITH THE RISK OF DEVELOPING VARIOUS FORMS OF CANCER, INCLUDING LUNG CANCER. MOREOVER, THERE IS EMERGING EVIDENCE THAT THESE EPIGENETIC MARKS AFFECT GENE EXPRESSION IN THE LUNG AND ARE ASSOCIATED WITH BENIGN LUNG DISEASES, SUCH AS ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND INTERSTITIAL LUNG DISEASE. TECHNOLOGICAL ADVANCES HAVE MADE IT FEASIBLE TO STUDY EPIGENETIC MARKS IN THE LUNG, AND IT IS ANTICIPATED THAT THIS KNOWLEDGE WILL ENHANCE OUR UNDERSTANDING OF THE DYNAMIC BIOLOGY IN THE LUNG AND LEAD TO THE DEVELOPMENT OF NOVEL DIAGNOSTIC AND THERAPEUTIC APPROACHES FOR OUR PATIENTS WITH LUNG DISEASE. 2011 7 2330 35 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 6735 38 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 9 396 30 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 10 2160 25 EPIGENETIC MECHANISMS IN ASTHMA. ASTHMA AND ALLERGIC DISEASES ARE AMONG THE MOST PREVALENT CHRONIC NONCOMMUNICABLE DISEASES OF CHILDHOOD, BUT THE UNDERLYING PATHOGENETIC MECHANISMS ARE POORLY UNDERSTOOD. BECAUSE EPIGENETIC MECHANISMS LINK GENE REGULATION TO ENVIRONMENTAL CUES AND DEVELOPMENTAL TRAJECTORIES, THEIR CONTRIBUTION TO ASTHMA AND ALLERGY PATHOGENESIS IS UNDER ACTIVE INVESTIGATION. DNA METHYLATION SIGNATURES ASSOCIATED WITH CONCURRENT DISEASE AND WITH THE DEVELOPMENT OF ASTHMA DURING CHILDHOOD ASTHMA HAVE BEEN IDENTIFIED, BUT THEIR SIGNIFICANCE IS NOT EASILY INTERPRETABLE. ON THE OTHER HAND, THE CHARACTERIZATION OF EARLY EPIGENETIC PREDICTORS OF ASTHMA POINTS TO A POTENTIAL ROLE OF EPIGENETIC MECHANISMS IN REGULATING THE INCEPTION OF, AND THE SUSCEPTIBILITY TO, THIS DISEASE. 2016 11 2049 26 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 12 2184 29 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 13 2586 30 EPIGENETICS OF PAIN MEDIATORS. PURPOSE OF REVIEW: THE FIELD OF EPIGENETICS CONTINUES ITS INFLUENTIAL RISE AS A MEANS TO BETTER UNDERSTAND AN ORGANISM'S UNIQUE DEVELOPMENTAL IDENTITY OVER A LIFESPAN. WHEREAS A GENOME IS CONSTANT AND UNCHANGING, AN EPIGENOME IS DYNAMIC AND ALTERABLE. EPIGENETIC CHANGES ARE IN RESPONSE TO INNUMERABLE INTERNAL AND EXTERNAL INFLUENCES INCLUDING ENVIRONMENTAL CHANGES SUCH AS DIET, EXERCISE, DISEASE, TOXINS, AND STRESS. EPIGENETICS IS OF PARTICULAR INTEREST IN THE MEDICAL RESEARCH COMMUNITY BOTH FOR THE POTENTIAL TO CAUSE DISEASE AND AS A TARGET FOR THERAPEUTIC INTERVENTIONS. THIS ARTICLE PROVIDES A SUCCINCT EXPLANATION OF THE POTENTIAL FOR EPIGENETICS TO INFLUENCE THE UNDERSTANDING OF PAIN AS WELL AS A REVIEW OF RELEVANT RESEARCH ON THE TOPIC. RECENT FINDINGS: STUDIES ON EPIGENETICS AND PAIN REMAIN LARGELY PRECLINICAL AND INVESTIGATE THE THEORETICAL ABILITY OF EPIGENETICS TO ALTER THE NOCICEPTIVE PATHWAYS BOTH IN THE PERIPHERY AND CENTRALLY. SIGNIFICANT EVIDENCE NOW EXISTS FOR THE ABILITY OF EPIGENETICS TO MODIFY BROADLY CATEGORIZED PAIN TYPES, INCLUDING INFLAMMATORY, NEUROPATHIC, VISCERAL, AND CANCER RELATED. SUMMARY: BOTH PATIENTS AND PROVIDERS RECOGNIZE THAT NOVEL MEDICATIONS FOR THE TREATMENT OF BOTH ACUTE AND CHRONIC PAIN CONDITIONS ARE SORELY NEEDED. THE UNDERSTANDING OF EPIGENETICS AND ITS INFLUENCE ON NOCICEPTION REMAINS IN RELATIVE INFANCY BUT EARLY EVIDENCE IS STRONG FOR POTENTIAL THERAPEUTIC BENEFITS TO TREAT THESE CONDITIONS. 2018 14 2984 30 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 15 5376 39 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 16 5534 31 ROLE OF AIRWAY EPITHELIAL CELLS IN THE DEVELOPMENT OF DIFFERENT ASTHMA PHENOTYPES. THE TERM (BRONCHIAL) ASTHMA DESCRIBES A DISORDER SYNDROME THAT COMPRISES SEVERAL DISEASE PHENOTYPES, ALL CHARACTERIZED BY CHRONIC INFLAMMATION IN THE BRONCHIAL EPITHELIUM, WITH A VARIETY OF SUBSEQUENT FUNCTIONAL CONSEQUENCES. THUS, THE EPITHELIUM IN THE CONDUCTING AIRWAYS IS THE MAIN LOCALIZATION OF THE COMPLEX PATHOLOGICAL CHANGES IN THE DISEASE. IN THIS REGARD, BRONCHIAL EPITHELIAL CELLS ARE NOT PASSIVELY AFFECTED BY INFLAMMATORY MECHANISMS INDUCED BY IMMUNOLOGICAL PROCESSES BUT RATHER ACTIVELY INVOLVED IN ALL STEPS OF DISEASE DEVELOPMENT FROM INITIATION AND PERPETUATION TO CHRONIFICATION. IN RECENT YEARS IT TURNED OUT THAT BRONCHIAL EPITHELIAL CELLS SHOW A HIGH LEVEL OF STRUCTURAL AND FUNCTIONAL DIVERSITY AND PLASTICITY WITH EPIGENETIC MECHANISMS PLAYING A CRUCIAL ROLE IN THE REGULATION OF THESE PROCESSES. THUS, IT IS QUITE REASONABLE THAT DIFFERENTIAL FUNCTIONAL ACTIVITIES OF THE BRONCHIAL EPITHELIUM ARE INVOLVED IN THE DEVELOPMENT OF DIFFERENT ASTHMA PHENOTYPES AND/OR STAGES OF DISEASE. THE CURRENT KNOWLEDGE ON THIS TOPIC WILL BE DISCUSSED IN THIS REVIEW ARTICLE. 2020 17 6740 31 WHEN GETOMICS MEETS AGING AND EXERCISE IN COPD. THE TERM GETOMICS HAS BEEN RECENTLY PROPOSED TO ILLUSTRATE THAT HUMAN HEALTH AND DISEASE ARE ACTUALLY THE FINAL OUTCOME OF MANY DYNAMIC, INTERACTING AND CUMULATIVE GENE (G) - ENVIRONMENT (E) INTERACTIONS THAT OCCUR THROUGH THE LIFETIME (T) OF THE INDIVIDUAL. ACCORDING TO THIS NEW PARADIGM, THE FINAL OUTCOME OF ANY GXE INTERACTIONS DEPENDS ON BOTH THE AGE OF THE INDIVIDUAL AT WHICH SUCH GXE INTERACTION OCCURS AS WELL AS ON THE PREVIOUS, CUMULATIVE HISTORY OF PREVIOUS GXE INTERACTIONS THROUGH THE INDUCTION OF EPIGENETIC CHANGES AND IMMUNE MEMORY (BOTH LASTING OVERTIME). FOLLOWING THIS CONCEPTUAL APPROACH, OUR UNDERSTANDING OF THE PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) HAS CHANGED DRAMATICALLY. TRADITIONALLY BELIEVED TO BE A SELF-INFLICTED DISEASE INDUCED BY TOBACCO SMOKING OCCURRING IN OLDER MEN AND CHARACTERIZED BY AN ACCELERATED DECLINE OF LUNG FUNCTION WITH AGE, NOW WE UNDERSTAND THAT THERE ARE MANY OTHER RISK FACTORS ASSOCIATED WITH COPD, THAT IT OCCURS ALSO IN FEMALES AND YOUNG INDIVIDUALS, THAT THERE ARE DIFFERENT LUNG FUNCTION TRAJECTORIES THROUGH LIFE, AND THAT COPD IS NOT ALWAYS CHARACTERIZED BY ACCELERATED LUNG FUNCTION DECLINE. IN THIS PAPER WE DISCUSS HOW A GETOMICS APPROACH TO COPD MAY OPEN NEW PERSPECTIVES TO BETTER UNDERSTAND ITS RELATIONSHIP WITH EXERCISE LIMITATION AND THE AGEING PROCESS. 2023 18 4126 29 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 19 3028 23 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 20 4392 29 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