1 2396 126 EPIGENETIC REPROGRAMMING IN PERIODONTAL DISEASE: DYNAMIC CROSSTALK WITH POTENTIAL IMPACT IN ONCOGENESIS. PERIODONTITIS IS A CHRONIC MULTIFACTORIAL IN FL AMMATORY DISEASE ASSOCIATED WITH MICROBIAL DYSBIOSIS AND CHARACTERIZED BY PROGRESSIVE DESTRUCTION OF THE PERIODONTAL TISSUES. SUCH CHRONIC INFECTIOUS INFLAMMATORY DISEASE IS RECOGNIZED AS A MAJOR PUBLIC HEALTH PROBLEM WORLDWIDE WITH MEASURABLE IMPACT IN SYSTEMIC HEALTH. IT HAS BECOME EVIDENT THAT THE PERIODONTAL DISEASE PHENOTYPES ARE NOT ONLY DETERMINED BY THE MICROBIOME EFFECT, BUT THE EXTENT OF THE TISSUE RESPONSE IS ALSO DRIVEN BY THE HOST GENOME AND EPIGENOME PATTERNS RESPONDING TO VARIOUS ENVIRONMENTAL EXPOSURES. MORE RECENTLY THERE IS MOUNTING EVIDENCE INDICATING THAT EPIGENETIC REPROGRAMMING IN RESPONSE TO COMBINED INTRINSIC AND ENVIRONMENTAL EXPOSURES, MIGHT BE PARTICULARLY RELEVANT DUE ITS PLASTICITY AND POTENTIAL APPLICATION TOWARDS PRECISION HEALTH. THE COMPLEX EPIGENETIC CROSSTALK IS REFLECTED IN THE PROGNOSIS AND PROGRESS OF PERIODONTAL DISEASES AND MAY ALSO LEAD TO A FAVORABLE LANDSCAPE FOR CANCER DEVELOPMENT. THIS REVIEW DISCUSSES EPIGENOMICS MODIFICATIONS FOCUSING ON THE ROLE OF DNA METHYLATION AND PATHWAYS LINKING MICROBIAL INFECTION AND INFLAMMATORY PATHWAYS, WHICH ARE ALSO ASSOCIATED WITH CARCINOGENESIS. THERE IS A MORE CLEAR VISION WHEREAS 'OMICS' TECHNOLOGIES APPLIED TO UNVEIL RELEVANT EPIGENETIC FACTORS COULD PLAY A SIGNIFICANT ROLE IN THE TREATMENT OF PERIODONTAL DISEASE IN A PERSONALIZED MODE, EVIDENCING THAT PUBLIC HEALTH APPROACH SHOULD COEXIST WITH PRECISION INDIVIDUALIZED TREATMENT. 2020 2 6288 43 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 3 4392 50 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 4 5929 44 TARGETING EPIGENETIC MECHANISMS IN PERIODONTAL DISEASES. EPIGENETIC FACTORS ARE HERITABLE GENOME MODIFICATIONS THAT POTENTIALLY IMPACT GENE TRANSCRIPTION, CONTRIBUTING TO DISEASE STATES. EPIGENETIC MARKS PLAY AN IMPORTANT ROLE IN CHRONIC INFLAMMATORY CONDITIONS, AS OBSERVED IN PERIODONTAL DISEASES, BY ALLOWING MICROBIAL PERSISTENCE OR BY PERMITTING MICROBIAL INSULT TO PLAY A ROLE IN THE SO-CALLED 'HIT-AND-RUN' INFECTIOUS MECHANISM, LEADING TO LASTING PATHOGEN INTERFERENCE WITH THE HOST GENOME. EPIGENETICS ALSO AFFECTS THE HEALTH SCIENCES BY PROVIDING A DYNAMIC MECHANISTIC FRAMEWORK TO EXPLAIN THE WAY IN WHICH ENVIRONMENTAL AND BEHAVIORAL FACTORS INTERACT WITH THE GENOME TO ALTER DISEASE RISK. IN THIS ARTICLE WE REVIEW CURRENT KNOWLEDGE OF EPIGENOME REGULATION IN LIGHT OF THE MULTIFACTORIAL NATURE OF PERIODONTAL DISEASES. WE DISCUSS EPIGENETIC TAGGING IN IDENTIFIED GENES, AND CONSIDER THE POTENTIAL IMPLICATIONS OF EPIGENETIC CHANGES ON HOST-MICROBIOME DYNAMICS IN CHRONIC INFLAMMATORY STATES AND IN RESPONSE TO ENVIRONMENTAL STRESSORS. THE MOST RECENT ADVANCES IN GENOMIC TECHNOLOGIES HAVE PLACED US IN A POSITION TO ANALYZE INTERACTION EFFECTS (EG, BETWEEN PERIODONTAL DISEASE AND TYPE 2 DIABETES MELLITUS), WHICH CAN BE INVESTIGATED THROUGH EPIGENOME-WIDE ASSOCIATION ANALYSIS. FINALLY, BECAUSE OF THE INDIVIDUALIZED TRAITS OF EPIGENETIC BIOMARKERS, PHARMACOEPIGENOMIC PERSPECTIVES ARE ALSO CONSIDERED AS POTENTIALLY NOVEL THERAPEUTIC APPROACHES FOR IMPROVING PERIODONTAL DISEASE STATUS. 2018 5 4273 40 MICROBIOTA AND EPIGENETICS: HEALTH IMPACT. EPIGENETIC CHANGES ASSOCIATED WITH DISEASE DEVELOPMENT AND PROGRESSIONS ARE OF INCREASING IMPORTANCE BECAUSE OF THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. SEVERAL EPIGENETIC CHANGES ASSOCIATED WITH CHRONIC METABOLIC DISORDERS HAVE BEEN STUDIED IN VARIOUS DISEASES. EPIGENETIC CHANGES ARE MOSTLY MODULATED BY ENVIRONMENTAL FACTORS, INCLUDING THE HUMAN MICROBIOTA LIVING IN DIFFERENT PARTS OF OUR BODIES. THE MICROBIAL STRUCTURAL COMPONENTS AND THE MICROBIALLY DERIVED METABOLITES DIRECTLY INTERACT WITH HOST CELLS, THEREBY MAINTAINING HOMEOSTASIS. MICROBIOME DYSBIOSIS, ON THE OTHER HAND, IS KNOWN TO PRODUCE ELEVATED LEVELS OF DISEASE-LINKED METABOLITES, WHICH MAY DIRECTLY AFFECT A HOST METABOLIC PATHWAY OR INDUCE EPIGENETIC CHANGES THAT CAN LEAD TO DISEASE DEVELOPMENT. DESPITE THEIR IMPORTANT ROLE IN HOST PHYSIOLOGY AND SIGNAL TRANSDUCTION, THERE HAS BEEN LITTLE RESEARCH INTO THE MECHANICS AND PATHWAYS ASSOCIATED WITH EPIGENETIC MODIFICATIONS. THIS CHAPTER FOCUSES ON THE RELATIONSHIP BETWEEN MICROBES AND THEIR EPIGENETIC EFFECTS IN DISEASED PATHOLOGY, AS WELL AS ON THE REGULATION AND METABOLISM OF THE DIETARY OPTIONS AVAILABLE TO THE MICROBES. FURTHERMORE, THIS CHAPTER ALSO PROVIDES A PROSPECTIVE LINK BETWEEN THESE TWO IMPORTANT PHENOMENA, TERMED "MICROBIOME AND EPIGENETICS." 2023 6 1871 45 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 7 2333 34 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 8 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 9 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 10 4393 31 MODIFIABLE RISK FACTORS IN PERIODONTITIS: AT THE INTERSECTION OF AGING AND DISEASE. CHRONIC INFLAMMATION IS A PROMINENT FEATURE OF AGING AND OF COMMON AGE-RELATED DISEASES, INCLUDING ATHEROSCLEROSIS, CANCER AND PERIODONTITIS. THIS VOLUME EXAMINES MODIFIABLE RISK FACTORS FOR PERIODONTITIS AND OTHER CHRONIC INFLAMMATORY DISEASES. ORAL BACTERIAL COMMUNITIES AND VIRAL INFECTIONS, PARTICULARLY WITH CYTOMEGALOVIRUS AND OTHER HERPESVIRUSES, ELICIT DISTINCT IMMUNE RESPONSES AND ARE CENTRAL IN THE INITIATION OF PERIODONTAL DISEASES. RISK OF DISEASE IS DYNAMIC AND CHANGES IN RESPONSE TO COMPLEX INTERACTIONS OF GENETIC, ENVIRONMENTAL AND STOCHASTIC FACTORS OVER THE LIFESPAN. MANY MODIFIABLE RISK FACTORS, SUCH AS SMOKING AND EXCESS CALORIC INTAKE, CONTRIBUTE TO INCREASES IN SYSTEMIC MARKERS OF INFLAMMATION AND CAN MODIFY GENE REGULATION THROUGH A VARIETY OF BIOLOGIC MECHANISMS (E.G. EPIGENETIC MODIFICATIONS). PERIODONTITIS AND OTHER COMMON CHRONIC INFLAMMATORY DISEASES SHARE MULTIPLE MODIFIABLE RISK FACTORS, SUCH AS TOBACCO SMOKING, PSYCHOLOGICAL STRESS AND DEPRESSION, ALCOHOL CONSUMPTION, OBESITY, DIABETES, METABOLIC SYNDROME AND OSTEOPOROSIS. INTERVENTIONS THAT TARGET MODIFIABLE RISK FACTORS HAVE THE POTENTIAL TO IMPROVE RISK PROFILES FOR PERIODONTITIS AS WELL AS FOR OTHER COMMON CHRONIC DISEASES. 2014 11 2558 42 EPIGENETICS IN SUSCEPTIBILITY, PROGRESSION, AND DIAGNOSIS OF PERIODONTITIS. PERIODONTITIS IS CHARACTERIZED BY IRREVERSIBLE DESTRUCTION OF PERIODONTAL TISSUE. AT PRESENT, THE ACCEPTED ETIOLOGY OF PERIODONTITIS IS BASED ON A THREE-FACTOR THEORY INCLUDING PATHOGENIC BACTERIA, HOST FACTORS, AND ACQUIRED FACTORS. PERIODONTITIS DEVELOPMENT USUALLY TAKES A DECADE OR LONGER AND IS THEREFORE CALLED CHRONIC PERIODONTITIS (CP). TO SEARCH FOR GENETIC FACTORS ASSOCIATED WITH CP, SEVERAL GENOME-WIDE ASSOCIATION STUDY (GWAS) ANALYSES WERE CONDUCTED; HOWEVER, POLYMORPHISMS ASSOCIATED WITH CP HAVE NOT BEEN IDENTIFIED. EPIGENETICS, ON THE OTHER HAND, INVOLVES ACQUIRED TRANSCRIPTIONAL REGULATORY MECHANISMS DUE TO REVERSIBLY ALTERED CHROMATIN ACCESSIBILITY. EPIGENETIC STATUS IS A CONDITION SPECIFIC TO EACH TISSUE AND CELL, MOSTLY DETERMINED BY THE RESPONSES OF HOST CELLS TO STIMULATIONS BY LOCAL FACTORS, LIKE BACTERIAL INFLAMMATION, AND SYSTEMIC FACTORS SUCH AS NUTRITION STATUS, METABOLIC DISEASES, AND HEALTH CONDITIONS. SIGNIFICANTLY, EPIGENETIC STATUS HAS BEEN LINKED WITH THE ONSET AND PROGRESSION OF SEVERAL ACQUIRED DISEASES. THUS, EPIGENETIC FACTORS IN PERIODONTAL TISSUES ARE ATTRACTIVE TARGETS FOR PERIODONTITIS DIAGNOSIS AND TREATMENTS. IN THIS REVIEW, WE INTRODUCE ACCUMULATING EVIDENCE TO REVEAL THE EPIGENETIC BACKGROUND EFFECTS RELATED TO PERIODONTITIS CAUSED BY GENETIC FACTORS, SYSTEMIC DISEASES, AND LOCAL ENVIRONMENTAL FACTORS, SUCH AS SMOKING, AND CLARIFY THE UNDERLYING MECHANISMS BY WHICH EPIGENETIC ALTERATION INFLUENCES THE SUSCEPTIBILITY OF PERIODONTITIS. 2022 12 1522 46 DNA METHYLATION CHANGE PROFILING OF COLORECTAL DISEASE: SCREENING TOWARDS CLINICAL USE. COLON CANCER REMAINS ONE OF THE LEADING CAUSES OF CANCER-RELATED DEATHS WORLDWIDE. TRANSFORMATION OF COLON EPITHELIAL CELLS INTO INVASIVE ADENOCARCINOMAS HAS BEEN WELL KNOWN TO BE DUE TO THE ACCUMULATION OF MULTIPLE GENETIC AND EPIGENETIC CHANGES. IN THE PAST DECADE, THE ETIOLOGY OF INFLAMMATORY BOWEL DISEASE (IBD) WHICH IS CHARACTERIZED BY CHRONIC INFLAMMATION OF THE INTESTINAL MUCOSA, WAS ONLY PARTIALLY EXPLAINED BY GENETIC STUDIES PROVIDING SUSCEPTIBILITY LOCI, BUT RECENTLY EPIGENETIC STUDIES HAVE PROVIDED CRITICAL EVIDENCES AFFECTING IBD PATHOGENESIS. OVER THE PAST DECADE, A DEEP UNDERSTANDING OF EPIGENETICS ALONG WITH TECHNOLOGICAL ADVANCES HAVE LED TO IDENTIFYING NUMEROUS GENES THAT ARE REGULATED BY PROMOTER DNA HYPERMETHYLATION IN COLORECTAL DISEASES. RECENT ADVANCES IN OUR UNDERSTANDING OF THE ROLE OF DNA METHYLATION IN COLORECTAL DISEASES COULD IMPROVE A MULTITUDE OF POWERFUL DNA METHYLATION-BASED BIOMARKERS, PARTICULARLY FOR USE AS DIAGNOSIS, PROGNOSIS, AND PREDICTION FOR THERAPEUTIC APPROACHES. THIS REVIEW FOCUSES ON THE EMERGING POTENTIAL FOR TRANSLATIONAL RESEARCH OF EPIGENETIC ALTERATIONS INTO CLINICAL UTILITY AS MOLECULAR BIOMARKERS. MOREOVER, THIS REVIEW DISCUSSES RECENT PROGRESS REGARDING THE IDENTIFICATION OF UNKNOWN HYPERMETHYLATED GENES IN COLON CANCERS AND IBD, AS WELL AS THEIR POSSIBLE ROLE IN CLINICAL PRACTICE, WHICH WILL HAVE IMPORTANT CLINICAL SIGNIFICANCE, PARTICULARLY IN THE ERA OF THE PERSONALIZED MEDICINE. 2021 13 6809 35 [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 14 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 15 3541 42 IMMUNOEPIGENETIC REGULATION OF INFLAMMATORY BOWEL DISEASE: CURRENT INSIGHTS INTO NOVEL EPIGENETIC MODULATIONS OF THE SYSTEMIC IMMUNE RESPONSE. THE IMMUNE SYSTEM AND ENVIRONMENTAL FACTORS ARE INVOLVED IN VARIOUS DISEASES, SUCH AS INFLAMMATORY BOWEL DISEASE (IBD), THROUGH THEIR EFFECT ON GENETICS, WHICH MODULATES IMMUNE CELLS. IBD ENCOMPASSES TWO MAIN PHENOTYPES, CROHN'S DISEASE, AND ULCERATIVE COLITIS, WHICH ARE MANIFESTED AS CHRONIC AND SYSTEMIC RELAPSE-REMITTING GASTROINTESTINAL TRACT DISORDERS WITH RISING GLOBAL INCIDENCE AND PREVALENCE. THE PATHOPHYSIOLOGY OF IBD IS COMPLEX AND NOT FULLY UNDERSTOOD. EPIGENETIC RESEARCH HAS RESULTED IN VALUABLE INFORMATION FOR UNRAVELING THE ETIOLOGY OF THIS IMMUNE-MEDIATED DISEASE. THUS, THE MAIN OBJECTIVE OF THE PRESENT REVIEW IS TO SUMMARIZE THE CURRENT FINDINGS ON THE ROLE OF EPIGENETIC MECHANISMS IN IBD TO SHED LIGHT ON THEIR POTENTIAL CLINICAL RELEVANCE. THIS REVIEW FOCUSES ON THE LATEST EVIDENCE REGARDING PERIPHERAL BLOOD MONONUCLEAR CELLS AND EPIGENETIC CHANGES IN HISTONE MODIFICATION, DNA METHYLATION, AND TELOMERE SHORTENING IN IBD. THE VARIOUS IDENTIFIED EPIGENETIC DNA PROFILES WITH CLINICAL VALUE IN IBD COULD BE USED AS BIOMARKERS FOR MORE ACCURATELY PREDICTING DISEASE DEVELOPMENT, TREATMENT RESPONSE, AND THERAPY-RELATED ADVERSE EVENTS. ULTIMATELY, THE INFORMATION PRESENTED HERE COULD BE OF POTENTIAL RELEVANCE FOR FUTURE CLINICAL PRACTICE IN DEVELOPING MORE EFFICIENT AND PRECISE MEDICINE TO IMPROVE THE QUALITY OF LIFE FOR PATIENTS WITH IBD. 2023 16 2282 41 EPIGENETIC REGULATION IN EXPOSOME-INDUCED TUMORIGENESIS: EMERGING ROLES OF NCRNAS. ENVIRONMENTAL FACTORS, INCLUDING POLLUTANTS AND LIFESTYLE, CONSTITUTE A SIGNIFICANT ROLE IN SEVERE, CHRONIC PATHOLOGIES WITH AN ESSENTIAL SOCIETAL, ECONOMIC BURDEN. THE MEASUREMENT OF ALL ENVIRONMENTAL EXPOSURES AND ASSESSING THEIR CORRELATION WITH EFFECTS ON INDIVIDUAL HEALTH IS DEFINED AS THE EXPOSOME, WHICH INTERACTS WITH OUR UNIQUE CHARACTERISTICS SUCH AS GENETICS, PHYSIOLOGY, AND EPIGENETICS. EPIGENETICS INVESTIGATES MODIFICATIONS IN THE EXPRESSION OF GENES THAT DO NOT DEPEND ON THE UNDERLYING DNA SEQUENCE. SOME STUDIES HAVE CONFIRMED THAT ENVIRONMENTAL FACTORS MAY PROMOTE DISEASE IN INDIVIDUALS OR SUBSEQUENT PROGENY THROUGH EPIGENETIC ALTERATIONS. VARIATIONS IN THE EPIGENETIC MACHINERY CAUSE A SPECTRUM OF DIFFERENT DISORDERS SINCE THESE MECHANISMS ARE MORE SENSITIVE TO THE ENVIRONMENT THAN THE GENOME, DUE TO THE INHERENT REVERSIBLE NATURE OF THE EPIGENETIC LANDSCAPE. SEVERAL EPIGENETIC MECHANISMS, INCLUDING MODIFICATIONS IN DNA (E.G., METHYLATION), HISTONES, AND NONCODING RNAS CAN CHANGE GENOME EXPRESSION UNDER THE EXOGENOUS INFLUENCE. NOTABLY, THE ROLE OF LONG NONCODING RNAS IN EPIGENETIC PROCESSES HAS NOT BEEN WELL EXPLORED IN THE CONTEXT OF EXPOSOME-INDUCED TUMORIGENESIS. IN THE PRESENT REVIEW, OUR SCOPE IS TO PROVIDE RELEVANT EVIDENCE INDICATING THAT EPIGENETIC ALTERATIONS MEDIATE THOSE DETRIMENTAL EFFECTS CAUSED BY EXPOSURE TO ENVIRONMENTAL TOXICANTS, FOCUSING MAINLY ON A MULTI-STEP REGULATION BY DIVERSE NONCODING RNAS SUBTYPES. 2022 17 2570 25 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 18 5003 47 PERIODONTITIS IS AN INFLAMMATORY DISEASE OF OXIDATIVE STRESS: WE SHOULD TREAT IT THAT WAY. PERIODONTITIS IS A HIGHLY PREVALENT DISEASE. AS IT PROGRESSES, IT CAUSES SERIOUS MORBIDITY IN THE FORM OF PERIODONTAL ABSCESSES AND TOOTH LOSS AND, IN THE LATTER STAGES, PAIN. IT IS ALSO NOW KNOWN THAT PERIODONTITIS IS STRONGLY ASSOCIATED WITH SEVERAL NONORAL DISEASES. THUS, PATIENTS WITH PERIODONTITIS ARE AT GREATER RISK FOR THE DEVELOPMENT AND/OR EXACERBATION OF DIABETES, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND CARDIOVASCULAR DISEASES, AMONG OTHER CONDITIONS. ALTHOUGH IT IS WITHOUT QUESTION THAT SPECIFIC GROUPS OF ORAL BACTERIA WHICH POPULATE DENTAL PLAQUE PLAY A CAUSATIVE ROLE IN THE DEVELOPMENT OF PERIODONTITIS, IT IS NOW THOUGHT THAT ONCE THIS DISEASE HAS BEEN TRIGGERED, OTHER FACTORS PLAY AN EQUAL, AND POSSIBLY MORE IMPORTANT, ROLE IN ITS PROGRESSION, PARTICULARLY IN SEVERE CASES OR IN CASES THAT PROVE DIFFICULT TO TREAT. IN THIS REGARD, WE ALLUDE TO THE HOST RESPONSE, SPECIFICALLY THE NOTION THAT THE HOST, ONCE INFECTED WITH ORAL PERIODONTAL PATHOGENIC BACTERIA, WILL MOUNT A DEFENSE RESPONSE MEDIATED LARGELY THROUGH THE INNATE IMMUNE SYSTEM. THE MOST ABUNDANT CELL TYPE OF THE INNATE IMMUNE SYSTEM - POLYMORPHONUCLEAR NEUTROPHILS - CAN, WHEN PROTECTING THE HOST FROM MICROBIAL INVASION, MOUNT A RESPONSE THAT INCLUDES UPREGULATION OF PROINFLAMMATORY CYTOKINES, MATRIX METALLOPROTEINASES, AND REACTIVE OXYGEN SPECIES, ALL OF WHICH THEN CONTRIBUTE TO THE TISSUE DAMAGE AND LOSS OF TEETH COMMONLY ASSOCIATED WITH PERIODONTITIS. OF THE MECHANISMS REFERRED TO HERE, WE SUGGEST THAT UPREGULATION OF REACTIVE OXYGEN SPECIES MIGHT PLAY ONE OF THE MOST IMPORTANT ROLES IN THE ESTABLISHMENT AND PROGRESSION OF PERIODONTITIS (AS WELL AS IN OTHER DISEASES OF INFLAMMATION) THROUGH THE DEVELOPMENT OF OXIDATIVE STRESS. IN THIS OVERVIEW, WE DISCUSS BOTH INNATE AND EPIGENETIC FACTORS (EG, DIABETES, SMOKING) THAT LEAD TO THE DEVELOPMENT OF OXIDATIVE STRESS. THIS OXIDATIVE STRESS THEN PROVIDES AN ENVIRONMENT CONDUCIVE TO THE DESTRUCTIVE PROCESSES OBSERVED IN PERIODONTITIS. THEREFORE, WE SHALL DESCRIBE SOME OF THE FUNDAMENTAL CHARACTERISTICS OF OXIDATIVE STRESS AND ITS EFFECTS ON THE PERIODONTIUM, DISCUSS THE DISEASES AND OTHER FACTORS THAT CAUSE OXIDATIVE STRESS, AND, FINALLY, REVIEW POTENTIALLY NOVEL THERAPEUTIC APPROACHES FOR THE MANAGEMENT (AND POSSIBLY EVEN THE REVERSAL) OF PERIODONTITIS, WHICH RELY ON THE USE OF THERAPIES, SUCH AS RESVERATROL AND OTHER ANTIOXIDANTS, THAT PROVIDE INCREASED ANTIOXIDANT ACTIVITY IN THE HOST. 2020 19 738 33 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 20 2543 46 EPIGENETICS IN LIVER DISEASE. EPIGENETICS IS A TERM THAT ENCOMPASSES A VARIETY OF REGULATORY PROCESSES THAT ARE ABLE TO CROSSTALK IN ORDER TO INFLUENCE GENE EXPRESSION AND CELL PHENOTYPE IN RESPONSE TO ENVIRONMENTAL CUES. A DEEP UNDERSTANDING OF EPIGENETICS OFFERS THE POTENTIAL FOR FRESH INSIGHTS INTO THE BASIS FOR COMPLEX CHRONIC DISEASES AND IMPROVED DIAGNOSTIC AND PROGNOSTIC TOOLS. MOREOVER, AS EPIGENETIC MODIFICATIONS ARE HIGHLY PLASTIC AND RESPONSIVE TO THE ENVIRONMENT, THERE IS MUCH EXCITEMENT AROUND THE THEME OF EPIGENETIC THERAPEUTICS, INCLUDING NOT ONLY NEW DRUGS BUT ALSO MORE INFORMED PATIENT ADVICE ON LIFESTYLE CHOICES AND THEIR IMPACT ON PATHOLOGY. THIS REVIEW BRIEFLY EXPLAINS THE MOLECULAR NATURE OF THE INDIVIDUAL REGULATORY PROCESS THAT CONSTITUTE EPIGENETICS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, CHROMATIN REMODELING, TRANSCRIPTIONAL CONTROL, AND NONCODING RNAS. THE WAYS IN WHICH THESE EPIGENETIC MECHANISMS INFLUENCE LIVER PHYSIOLOGY AND DISEASE WILL BE CONSIDERED IN DETAIL, PARTICULARLY IN THE CONTEXT OF CANCER, FIBROSIS, AND NONALCOHOLIC STEATOHEPATITIS. THE CURRENT LIMITATIONS ASSOCIATED WITH EPIGENETIC PROFILING AND THERAPEUTICS IN LIVER DISEASE ARE DISCUSSED, AS IS THE INTRIGUING POSSIBILITY THAT ENVIRONMENTAL-INDUCED EPIGENETIC CHANGES MAY BECOME STABLE AND HERITABLE. CONCLUSION: THE AIM OF THE REVIEW IS TO INFORM HEPATOLOGISTS OF THE EMERGING KEY EPIGENETIC IDEAS OF RELEVANCE TO LIVER DISEASES THAT ARE HIGHLY LIKELY TO FORM A COMPONENT OF PATIENT MANAGEMENT AND CARE IN THE NEXT DECADE. 2014