1 279 120 AGE-RELATED MACULAR DEGENERATION: FROM EPIGENETICS TO THERAPEUTIC IMPLICATIONS. ABERRANT REGULATION OF EPIGENETIC MECHANISMS, INCLUDING THE TWO MOST COMMON TYPES; DNA METHYLATION AND HISTONE MODIFICATION HAVE BEEN IMPLICATED IN COMMON CHRONIC PROGRESSIVE CONDITIONS, INCLUDING ALZHEIMER DISEASE, CARDIOVASCULAR DISEASE, AND AGE-RELATED MACULAR DEGENERATION (AMD). ALL THESE CONDITIONS ARE COMPLEX, MEANING THAT ENVIRONMENTAL FACTORS, GENETIC FACTORS, AND THEIR INTERACTIONS PLAY A ROLE IN DISEASE PATHOPHYSIOLOGY. ALTHOUGH GENOME WIDE ASSOCIATION STUDIES (GWAS), AND STUDIES ON TWINS DEMONSTRATE THE GENETIC/HEREDITARY COMPONENT TO THESE COMPLEX DISEASES, INCLUDING AMD, THIS CONTRIBUTION IS MUCH LESS THAN 100%. MOREOVER, THE CONTRIBUTION OF THE HEREDITARY COMPONENT DECREASES IN THE ADVANCED, LATER ONSET FORMS OF THESE CHRONIC DISEASES INCLUDING AMD. THIS UNDERSCORES THE NEED TO ELUCIDATE HOW THE GENETIC AND ENVIRONMENTAL FACTORS FUNCTION TO EXERT THEIR INFLUENCE ON DISEASE PATHOPHYSIOLOGY. BY TEASING OUT EPIGENETIC MECHANISMS AND HOW THEY EXERT THEIR INFLUENCE ON AMD, THERAPEUTIC TARGETS CAN BE TAILORED TO PREVENT AND/OR SLOW DOWN DISEASE PROGRESSION. EPIGENETIC STUDIES THAT INCORPORATE WELL-CHARACTERIZED PATIENT TISSUE SAMPLES (INCLUDING AFFECTED TISSUES AND PERIPHERAL BLOOD), SIMILAR TO THOSE RELEVANT TO GENE EXPRESSION STUDIES, ALONG WITH GENETIC AND EPIDEMIOLOGICAL INFORMATION, CAN BE THE FIRST STEP IN DEVELOPING APPROPRIATE FUNCTIONAL ASSAYS TO VALIDATE FINDINGS AND IDENTIFY POTENTIAL THERAPIES. 2021 2 738 34 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 3 3404 41 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 4 2333 32 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 5 3038 38 GENOME ENGINEERING FOR OSTEOARTHRITIS: FROM DESIGNER CELLS TO DISEASE-MODIFYING DRUGS. BACKGROUND: OSTEOARTHRITIS (OA) IS A HIGHLY PREVALENT DEGENERATIVE JOINT DISEASE INVOLVING JOINT CARTILAGE AND ITS SURROUNDING TISSUES. OA IS THE LEADING CAUSE OF PAIN AND DISABILITY WORLDWIDE. AT PRESENT, THERE ARE NO DISEASE-MODIFYING OA DRUGS, AND THE PRIMARY THERAPIES INCLUDE EXERCISE AND NONSTEROIDAL ANTI-INFLAMMATORY DRUGS UNTIL TOTAL JOINT REPLACEMENT AT THE END-STAGE OF THE DISEASE. METHODS: IN THIS REVIEW, WE SUMMARIZED THE CURRENT STATE OF KNOWLEDGE IN GENETIC AND EPIGENETIC ASSOCIATIONS AND RISK FACTORS FOR OA AND THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. RESULTS: GENOME-WIDE ASSOCIATION STUDIES AND ANALYSIS OF EPIGENETIC MODIFICATIONS (SUCH AS MIRNA EXPRESSION, DNA METHYLATION AND HISTONE MODIFICATIONS) CONDUCTED ACROSS VARIOUS POPULATIONS SUPPORT THE NOTION THAT THERE IS A GENETIC BASIS FOR CERTAIN SUBSETS OF OA PATHOGENESIS. CONCLUSION: WITH RECENT ADVANCES IN THE DEVELOPMENT OF GENOME EDITING TECHNOLOGIES SUCH AS THE CRISPR-CAS9 SYSTEM, THESE GENETIC AND EPIGENETIC ALTERNATIONS IN OA CAN BE USED AS PLATFORMS FROM WHICH POTENTIAL BIOMARKERS FOR THE DIAGNOSIS, PROGNOSIS, DRUG RESPONSE, AND DEVELOPMENT OF POTENTIAL PERSONALIZED THERAPEUTIC TARGETS FOR OA CAN BE APPROACHED. FURTHERMORE, GENOME EDITING HAS ALLOWED THE DEVELOPMENT OF "DESIGNER" CELLS, WHEREBY THE RECEPTORS, GENE REGULATORY NETWORKS, OR TRANSGENES CAN BE MODIFIED AS A BASIS FOR NEW CELL-BASED THERAPIES. 2019 6 3706 42 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 7 1871 41 EMERGING ROLE OF EPIGENETICS IN EXPLAINING RELATIONSHIP OF PERIODONTITIS AND CARDIOVASCULAR DISEASES. CARDIOVASCULAR DISEASES SUCH AS ISCHEMIC HEART DISEASES OR STROKE ARE AMONG THE LEADING CAUSE OF DEATHS GLOBALLY, AND EVIDENCE SUGGESTS THAT THESE DISEASES ARE MODULATED BY A MULTIFACTORIAL AND COMPLEX INTERPLAY OF GENETIC, ENVIRONMENTAL, AND LIFESTYLE FACTORS. GENETIC PREDISPOSITION AND CHRONIC EXPOSURE TO MODIFIABLE RISK FACTORS HAVE BEEN EXPLORED TO BE INVOLVED IN THE PATHOPHYSIOLOGY OF CVD. ENVIRONMENTAL FACTORS CONTRIBUTE TO AN INDIVIDUAL'S PROPENSITY TO DEVELOP MAJOR CARDIOVASCULAR RISK FACTORS THROUGH EPIGENETIC MODIFICATIONS OF DNA AND HISTONES VIA MIRNA REGULATION OF PROTEIN TRANSLATION THAT ARE TYPES OF EPIGENETIC MECHANISMS AND PARTICIPATE IN DISEASE DEVELOPMENT. PERIODONTAL DISEASE (PD) IS ONE OF THE MOST COMMON ORAL DISEASES IN HUMANS THAT IS CHARACTERIZED BY LOW-GRADE INFLAMMATION AND HAS BEEN SHOWN TO INCREASE THE RISK OF CVDS. RISK FACTORS INVOLVED IN PD AND CVD ARE DETERMINED BOTH GENETICALLY AND BEHAVIORALLY. PERIODONTAL DISEASES SUCH AS CHRONIC INFLAMMATION PROMOTE DNA METHYLATION. EPIGENETIC MODIFICATIONS INVOLVED IN THE INITIATION AND PROGRESSION OF ATHEROSCLEROSIS PLAY AN ESSENTIAL ROLE IN PLAQUE DEVELOPMENT AND VULNERABILITY. EPIGENETICS HAS OPENED A NEW WORLD TO UNDERSTAND AND MANAGE HUMAN DISEASES, INCLUDING CVDS AND PERIODONTAL DISEASES. GENETIC MEDICINE HAS STARTED A NEW ERA OF EPIGENETICS TO OVERCOME HUMAN DISEASES WITH VARIOUS NEW METHODOLOGY. EPIGENETIC PROFILING MAY AID IN BETTER DIAGNOSIS AND STRATIFICATION OF PATIENTS SHOWING POTENTIAL PREDISPOSED STATES FOR DISEASE. A BETTER UNDERSTANDING OF THE EXACT REGULATORY MECHANISMS OF EPIGENETIC PATHWAYS DRIVING INFLAMMATION IS SLOWLY EMERGING AND WILL AID IN DEVELOPING NOVEL TOOLS FOR THE TREATMENT OF DISEASE. 2021 8 6629 30 UNDERSTANDING THE HUMAN AGING PROTEOME USING EPIDEMIOLOGICAL MODELS. HUMAN AGING IS A COMPLEX MULTIFACTORIAL PROCESS ASSOCIATED WITH A DECLINE OF PHYSICAL AND COGNITIVE FUNCTION AND HIGH SUSCEPTIBILITY TO CHRONIC DISEASES, INFLUENCED BY GENETIC, EPIGENETIC, ENVIRONMENTAL, AND DEMOGRAPHIC FACTORS. THIS CHAPTER WILL PROVIDE AN OVERVIEW ON THE USE OF EPIDEMIOLOGICAL MODELS WITH PROTEOMICS DATA AS A METHOD THAT CAN BE USED TO IDENTIFY FACTORS THAT MODULATE THE AGING PROCESS IN HUMANS. THIS IS DEMONSTRATED WITH PROTEOMICS DATA FROM HUMAN PLASMA AND SKELETAL MUSCLE, WHERE THE COMBINATION WITH EPIDEMIOLOGICAL MODELS IDENTIFIED A SET OF MITOCHONDRIAL, SPLICEOSOME, AND SENESCENCE PROTEINS AS WELL AS THE ROLE OF ENERGETIC PATHWAYS SUCH AS GLYCOLYSIS, AND ELECTRON TRANSPORT PATHWAYS THAT REGULATE THE AGING PROCESS. 2022 9 2570 29 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 10 6288 45 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 11 3028 32 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 12 2404 36 EPIGENETIC RESEARCH IN MULTIPLE SCLEROSIS: PROGRESS, CHALLENGES, AND OPPORTUNITIES. MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY AND DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM. MS LIKELY RESULTS FROM A COMPLEX INTERPLAY BETWEEN PREDISPOSING CAUSAL GENE VARIANTS (THE STRONGEST INFLUENCE COMING FROM HLA CLASS II LOCUS) AND ENVIRONMENTAL RISK FACTORS SUCH AS SMOKING, INFECTIOUS MONONUCLEOSIS, AND LACK OF SUN EXPOSURE/VITAMIN D. HOWEVER, LITTLE IS KNOWN ABOUT THE MECHANISMS UNDERLYING MS DEVELOPMENT AND PROGRESSION. MOREOVER, THE CLINICAL HETEROGENEITY AND VARIABLE RESPONSE TO TREATMENT REPRESENT ADDITIONAL CHALLENGES TO A COMPREHENSIVE UNDERSTANDING AND EFFICIENT TREATMENT OF DISEASE. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION AND HISTONE POSTTRANSLATIONAL MODIFICATIONS, INTEGRATE INFLUENCES FROM THE GENES AND THE ENVIRONMENT TO REGULATE GENE EXPRESSION ACCORDINGLY. STUDYING EPIGENETIC MODIFICATIONS, WHICH ARE STABLE AND REVERSIBLE, MAY PROVIDE AN ALTERNATIVE APPROACH TO BETTER UNDERSTAND AND MANAGE DISEASE. WE HERE AIM TO REVIEW FINDINGS FROM EPIGENETIC STUDIES IN MS AND FURTHER DISCUSS THE CHALLENGES AND CLINICAL OPPORTUNITIES ARISING FROM EPIGENETIC RESEARCH, MANY OF WHICH APPLY TO OTHER DISEASES WITH SIMILAR COMPLEX ETIOLOGY. A GROWING BODY OF EVIDENCE SUPPORTS A ROLE OF EPIGENETIC PROCESSES IN THE MECHANISMS UNDERLYING IMMUNE PATHOGENESIS AND NERVOUS SYSTEM DYSFUNCTION IN MS. HOWEVER, DISPARITIES BETWEEN STUDIES SHED LIGHT ON THE NEED TO CONSIDER POSSIBLE CONFOUNDERS AND METHODOLOGICAL LIMITATIONS FOR A BETTER INTERPRETATION OF THE DATA. NEVERTHELESS, TRANSLATIONAL USE OF EPIGENETICS MIGHT OFFER NEW OPPORTUNITIES IN EPIGENETIC-BASED DIAGNOSTICS AND THERAPEUTIC TOOLS FOR A PERSONALIZED CARE OF MS PATIENTS. 2017 13 5376 47 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 14 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 15 396 33 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 16 2282 39 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 17 2154 33 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 18 2027 39 EPIGENETIC CHANGES IN CHRONIC INFLAMMATORY DISEASES. THE NUMBER OF PEOPLE DIAGNOSED WITH CHRONIC INFLAMMATORY DISEASES HAS INCREASED NOTEWORTHY IN THE LAST 40 YEARS. SPONDYLOARTHRITIS (SPA), INFLAMMATORY BOWEL DISEASES (IBD), AND PSORIASIS ARE THE MOST FREQUENT CHRONIC INFLAMMATORY DISEASES, RESULTING FROM A COMBINATION OF GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATIONS INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND SMALL AND LONG NONCODING RNAS. THEY ARE INFLUENCED BY ENVIRONMENTAL EXPOSURE, LIFE-STYLE, AND AGING AND HAVE RECENTLY BEEN SHOWN TO BE ALTERED IN MANY COMPLEX DISEASES INCLUDING INFLAMMATORY DISEASES. WHILE EPIGENETIC MODIFICATIONS HAVE BEEN WELL CHARACTERIZED IN OTHER DISEASES SUCH AS CANCER AND AUTOIMMUNE DISEASES, KNOWLEDGE ON CHANGES IN INFLAMMATORY DISEASES IS LAGGING BEHIND WITH SOME DISEASE-SPECIFIC DIFFERENCES. WHILE THE DNA METHYLATION PROFILE OF DIFFERENT CELL TYPES IN PATIENTS WITH IBD HAS BEEN RELATIVELY WELL DESCRIBED, LESS IS KNOWN ON CHANGES IMPLICATED IN PSORIASIS, AND NO SYSTEMATIC GENOME-WIDE STUDIES HAVE SO FAR BEEN PERFORMED IN SPA. IN THIS CHAPTER, WE REVIEW IN DETAIL THE REPORTED CHANGES IN PATTERNS OF DNA METHYLATION AND POSTTRANSLATIONAL HISTONE MODIFICATIONS IN CHRONIC INFLAMMATORY DISEASES HIGHLIGHTING POTENTIAL CONNECTIONS BETWEEN DISEASE-ASSOCIATED PATHOPHYSIOLOGICAL CHANGES SUCH AS THE DYSBIOSIS OF THE MICROBIOME OR GENETIC VARIATIONS ASSOCIATED WITH DISEASE SUSCEPTIBILITY AND THE EPIGENOME. WE ALSO DISCUSS IMPORTANT PARAMETERS OF MEANINGFUL EPIGENETIC STUDIES SUCH AS THE USE OF WELL DEFINED, DISEASE-RELEVANT CELL POPULATIONS, AND ELUDE ON THE POTENTIAL FUTURE OF ENGINEERING OF THE EPIGENOME IN INFLAMMATORY DISEASES. 2017 19 3108 26 GENOMICS OF PAIN IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) ACCOUNTS FOR THE MAJORITY OF THE DISEASE BURDEN FOR MUSCULOSKELETAL DISORDERS AND IS ONE OF THE LEADING CAUSES OF DISABILITY WORLDWIDE. THIS DISABILITY IS THE RESULT NOT OF THE CARTILAGE LOSS THAT DEFINES OA RADIOGRAPHICALLY, BUT OF THE CHRONIC PAIN WHOSE PRESENCE DEFINES SYMPTOMATIC OA. IT IS BECOMING CLEAR THAT MANY GENES, EACH WITH A SMALL EFFECT SIZE, CONTRIBUTE TO THE RISK OF DEVELOPING OA. HOWEVER, THE GENETICS OF OA PAIN ARE ONLY JUST STARTING TO BE EXPLORED. THIS REVIEW WILL DESCRIBE THE FIRST GENES TO HAVE BEEN IDENTIFIED IN GENOMIC STUDIES OF OA PAIN, AS WELL AS THE POSSIBLE DUAL ROLES OF GENES PREVIOUSLY IDENTIFIED IN GENOMIC STUDIES OF OA IN THE CONTEXT OF PAIN. DIFFICULTIES ASSOCIATED WITH ATTEMPTING TO CHARACTERISE THE GENETICS OF OA PAIN WILL BE DISCUSSED AND PROMISING FUTURE AVENUES OF RESEARCH INTO GENETIC AND EPIGENETIC FACTORS AFFECTING OA PAIN DESCRIBED. 2013 20 6199 37 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