1 2558 118 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 2 6288 44 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 41 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 5003 49 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 5 523 41 ASSOCIATIONS BETWEEN PERIODONTITIS AND SYSTEMIC INFLAMMATORY DISEASES: RESPONSE TO TREATMENT. THERE IS A SIGNIFICANT PREVALENCE OF SUBJECTS WITH PERIODONTITIS PRESENTING WITH OTHER INFLAMMATORY CONDITIONS SUCH AS CORONARY HEART DISEASE, INSULIN RESISTANCE AND ARTHRITIS. THIS PATTERN OF DISEASE PRESENTATION UNDERSCORES THE IMPORTANCE OF INFLAMMATORY LOADING FROM CHRONIC DISEASES, IN DRIVING THEIR PATHOGENESES IN A MULTIDIRECTIONAL MANNER. PRO-INFLAMMATORY CYTOKINES AND OTHER AGENTS PLAY AN IMPORTANT ROLE IN THIS PROCESS; FOR EXAMPLE, A SINGLE NUCLEOTIDE POLYMORPHISM OF THE TNF-ALPHA GENE IS ASSOCIATED WITH SIGNIFICANT PERIODONTAL ATTACHMENT LOSS IN PATIENTS WITH CORONARY HEART DISEASE. CHANGES IN GENE EXPRESSION ASSOCIATED WITH INFLAMMATION AND LIPID METABOLISM IN RESPONSE TO ORAL INFECTION WITH THE PERIODONTAL PATHOGEN PORPHYROMONAS GINGIVALIS (PG) HAVE BEEN DEMONSTRATED IN MOUSE MODELS, INDEPENDENT OF THE DEMONSTRATION OF ATHEROSCLEROTIC LESIONS. INSULIN RESISTANCE IS CONSIDERED TO BE A CHRONIC LOW-GRADE INFLAMMATORY CONDITION, ASSOCIATED WITH ALTERED GLUCOSE TOLERANCE, HYPERTRIGLYCERIDEMIA, CENTRAL OBESITY AND CORONARY HEART DISEASE. IT IS ACCOMPANIED BY ELEVATED LEVELS OF IL-1, IL-6 AND TNF-ALPHA ALSO RELEVANT TO THE PROGRESSION OF PERIODONTITIS. THERE IS EVIDENCE THAT UNCONTROLLED PERIODONTAL DISEASE CONTRIBUTES TO MAINTENANCE OF SYSTEMIC DISEASES, INCLUDING RHEUMATOID ARTHRITIS (RA), WITH INCREASED RISK OF PERIODONTITIS IN SUBJECTS WITH RA. THE PERIODONTAL PATHOGEN PG IS SIGNIFICANT IN CONTRIBUTING TO CITRULLINATION OF PROTEINS RESULTING IN IMMUNE DYSREGULATION AND AUTOIMMUNE RESPONSES, SEEN IN RA. HOWEVER, THEY ARE BOTH MULTIFACTORIAL CHRONIC DISEASES WITH COMPLEX ETIOPATHOGENESES THAT AFFECT THEIR PRESENTATION. CONSISTENT BUT WEAK ASSOCIATIONS ARE SEEN FOR SURROGATE MARKERS OF PERIODONTITIS SUCH AS TOOTH LOSS, WITH MULTIPLE SYSTEMIC CONDITIONS. EFFECTIVE TREATMENT OF PERIODONTITIS WOULD BE IMPORTANT IN REDUCING SYSTEMIC INFLAMMATORY LOADING FROM CHRONIC LOCAL INFLAMMATION AND IN ACHIEVING SYSTEMIC HEALTH. LACK OF A CONSISTENT CAUSE AND EFFECT RELATIONSHIP IN ALL SUBJECTS WOULD BE INFLUENCED BY GENETIC, EPIGENETIC AND OTHER SUBJECT VARIABLES, ALTHOUGH THERE ARE CLEAR MECHANISMS THAT LINK THE ASSOCIATIONS. THIS ARTICLE INCLUDES AN APPRAISAL OF PATENTS AND THEIR APPLICATIONS. 2013 6 2396 42 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 7 4393 32 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 8 2501 37 EPIGENETICS AND ITS ROLE IN PERIODONTAL DISEASES: A STATE-OF-THE-ART REVIEW. THE IMMUNE RESPONSE TO ORAL BACTERIA AND THE SUBSEQUENT ACTIVATION OF INFLAMMATORY SIGNALING IS NOT ONLY DEPENDENT ON GENETIC FACTORS. THE IMPORTANCE OF SO-CALLED EPIGENETIC MECHANISMS PRESENTS ADDITIONAL REGULATORY PATHWAYS OF GENES INVOLVED IN MAINTAINING CHRONIC INFLAMMATION, INCLUDING GINGIVITIS AND PERIODONTITIS. THE TERM EPIGENETICS RELATES TO CHANGES IN GENE EXPRESSION THAT ARE NOT ENCODED IN THE DNA SEQUENCE ITSELF AND INCLUDE CHEMICAL ALTERATIONS OF DNA AND ITS ASSOCIATED PROTEINS. THESE CHANGES LEAD TO REMODELING OF THE CHROMATIN AND SUBSEQUENT ACTIVATION OR INACTIVATION OF A GENE. EPIGENETIC MECHANISMS HAVE BEEN FOUND TO CONTRIBUTE TO DISEASE, INCLUDING CANCER AND AUTOIMMUNE OR INFLAMMATORY DISEASES. IN THIS STATE-OF-THE ART REVIEW, THE AUTHORS PROVIDE THE LATEST FINDINGS ON THE INVOLVEMENT OF EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT OF PERIODONTAL DISEASE AND PRESENT EMERGING THERAPEUTIC STRATEGIES AIMED AT EPIGENETIC TARGETS (EPIDRUGS) ASSOCIATED WITH THE DISRUPTION OF TISSUE HOMEOSTASIS AND THE DEVELOPMENT OF PERIODONTITIS. 2015 9 6809 37 [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 10 1606 33 DNA METHYLATION, BACTERIA AND AIRWAY INFLAMMATION: LATEST INSIGHTS. PURPOSE OF REVIEW: DNA METHYLATION IS AN EPIGENETIC MECHANISM THAT HAS BEEN IMPLICATED IN THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES BY REGULATING DIFFERENTIATION, PROLIFERATION, APOPTOSIS, AND ACTIVATION OF IMMUNE CELLS. CHANGES IN THE METHYLATION STATUS OF RELEVANT GENES HAVE BEEN LINKED TO THE ORIGIN, PERPETUATION, AND SEVERITY OF AIRWAY DISEASES. THE DNA METHYLATION PROFILE CAN BE ALSO MODIFIED BY THE ACTION OF VIRAL AND BACTERIAL COLONIZATION. BACTERIA AND SPECIALLY STAPHYLOCOCCUS AUREUS TOXINS ARE RECOGNIZED INFLAMMATORY AMPLIFYING FACTORS IN BOTH LOWER AND UPPER AIRWAY CHRONIC DISEASES. THIS REVIEW SUMMARIZES THE EXISTENT KNOWLEDGE ABOUT THE ROLE OF DNA METHYLATION CHANGES IN CHRONIC AIRWAY DISEASES AND THE CONTRIBUTION OF BACTERIAL INFECTION ON THIS EVENT. RECENT FINDINGS: IT HAS BEEN DEMONSTRATED THAT CHANGES IN DNA METHYLATION, EITHER INTRINSIC OR INDUCED BY ALLERGEN OR INFECTION, MAY BE LINKED TO THE PATHOGENESIS OF ASTHMA AND ALLERGY. THESE CHANGES IN METHYLATION MAY SUPPRESS THE PRODUCTION OF ANTI-INFLAMMATORY MEDIATORS AND INCREASE THE SURVIVAL AND ACTIVATION OF PRO-INFLAMMATORY CELLS, AS WELL AS MODIFY THE IMMUNE RESPONSE IN RESPONSE TO BACTERIAL INFECTION, INCREASING THEIR SURVIVAL AND PATHOGENICITY WITHIN THE INFECTED ORGANISM. SUMMARY: UNDERSTANDING THE INTRINSIC EPIGENETIC MECHANISMS, AS WELL AS THE EFFECT OF ENVIRONMENT -FOR EXAMPLE, BACTERIAL INFECTION IN THE PATHOGENESIS OF AIRWAYS DISEASES - WILL GREATLY IMPROVE THE MANAGEMENT AND THE DIAGNOSIS OF THESE DISEASES. 2015 11 3706 37 INFLUENCE OF GENETICS ON DISEASE SUSCEPTIBILITY AND PROGRESSION. FOR MANY CHRONIC DISEASES, THE INFLUENCE OF GENETICS IS COMPLEX AND PHENOTYPES DO NOT CONFORM TO SIMPLE MENDELIAN PATTERNS OF INHERITANCE. DISCUSSED HERE ARE TWO TYPES OF GENETIC INFLUENCES ON HEALTHY AGING. THE FIRST INVOLVES VARIATION IN THE GENE SEQUENCE ITSELF AND HOW THIS MAY INFLUENCE DISEASE SUSCEPTIBILITY, PROGRESSION, AND SEVERITY, INTERACTING WITH OTHER RECOGNIZED RISK FACTORS. THE SECOND INVOLVES EPIGENETIC REGULATORY MECHANISMS THAT MAY POTENTIALLY PROVIDE INSIGHT INTO HOW ENVIRONMENTAL INFLUENCES AFFECT THE EXPRESSED GENOME, THUS IMPROVING OUR UNDERSTANDING OF THE GENETIC MECHANISMS UNDERLYING MULTIFACTORIAL DISEASES. THE INTERLEUKIN-1 FAMILY OF CYTOKINES CAN BE USED TO ILLUSTRATE HOW GENETIC SEQUENCE VARIATION MAY AFFECT SUCH DISEASES. THIS CYTOKINE FAMILY PLAYS A KEY ROLE IN MEDIATING INFLAMMATION, WHICH IS NOW UNDERSTOOD TO BE A CENTRAL COMPONENT OF A GROWING NUMBER OF CHRONIC DISEASES. RECENT WORK HAS REVEALED MANY SEQUENCE VARIATIONS IN THE REGULATORY DNA OF GENES ENCODING IMPORTANT MEMBERS OF THE INTERLEUKIN-1 FAMILY, AND THESE VARIATIONS ARE ASSOCIATED WITH DIFFERENTIAL EFFECTS ON THE INFLAMMATORY RESPONSE. THE INTERACTIONS OF ENVIRONMENTAL FACTORS WITH BOTH DNA SEQUENCE VARIATIONS AND EPIGENETIC MODIFICATIONS ARE LIKELY TO DETERMINE THE PHENOTYPES OF MULTIFACTORIAL DISEASES OF AGING AS WELL AS THE PHENOTYPE OF HEALTHY AGING. 2007 12 6128 25 THE EPIGENETIC PARADIGM IN PERIODONTITIS PATHOGENESIS. EPIGENOME REFERS TO "EPI" MEANING OUTSIDE THE "GENOME." EPIGENETICS IS THE FIELD OF STUDY OF THE EPIGENOME. EPIGENETIC MODIFICATIONS INCLUDE CHANGES IN THE PROMOTER CPG ISLANDS, MODIFICATIONS OF HISTONE PROTEIN STRUCTURE, POSTTRANSLATIONAL REPRESSION BY MICRO-RNA WHICH CONTRIBUTES TO THE ALTERATION OF GENE EXPRESSION. EPIGENETICS PROVIDES AN UNDERSTANDING OF THE ROLE OF GENE-ENVIRONMENT INTERACTIONS ON DISEASE PHENOTYPE ESPECIALLY IN COMPLEX MULTIFACTORIAL DISEASES. PERIODONTITIS IS A CHRONIC INFLAMMATORY DISORDER THAT AFFECTS THE SUPPORTING STRUCTURES OF THE TOOTH. THE ROLE OF THE GENOME (IN TERMS OF GENETIC POLYMORPHISMS) IN PERIODONTITIS PATHOGENESIS HAS BEEN EXAMINED IN NUMEROUS STUDIES, AND CHRONIC PERIODONTITIS HAS BEEN ESTABLISHED AS A POLYGENIC DISORDER. THE POTENTIAL ROLE OF EPIGENETIC MODIFICATIONS IN THE VARIOUS FACETS OF PATHOGENESIS OF PERIODONTITIS IS DISCUSSED IN THIS PAPER BASED ON THE AVAILABLE LITERATURE. 2015 13 5929 38 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 14 3681 36 INFLAMMATION, DNA METHYLATION AND COLITIS-ASSOCIATED CANCER. INFLAMMATION CAN RESULT FROM A RANGE OF SOURCES INCLUDING MICROBIAL INFECTIONS, EXPOSURE TO ALLERGENS AND TOXIC CHEMICALS, AUTOIMMUNE DISEASE AND OBESITY. A WELL-BALANCED IMMUNE RESPONSE CAN BE ANTI-TUMORIGENIC; HOWEVER, A SUSTAINED OR CHRONIC INFLAMMATORY RESPONSE IS GENERALLY HARMFUL AS THE IMMUNE RESPONSE BECOMES DISTORTED. A CAUSAL LINK BETWEEN CHRONIC INFLAMMATION AND CANCER IS NOW WELL ACCEPTED AND MANY CHRONICALLY INFLAMED ORGANS OF THE GASTROINTESTINAL TRACT SHOW THIS ASSOCIATION. FOR EXAMPLE, PATIENTS WITH INFLAMMATORY BOWEL DISEASE (IBD), INCLUDING BOTH ULCERATIVE COLITIS AND CROHN'S DISEASE, HAVE A 2- TO 3-FOLD GREATER LIFETIME RISK OF DEVELOPING COLORECTAL CANCER COMPARED WITH THE GENERAL POPULATION. THE DEVELOPMENT OF COLITIS-ASSOCIATED CANCER (CAC) IS THOUGHT TO BE MULTIFACETED AND IS PROBABLY DUE TO A COMBINATION OF GENETIC FACTORS, EPIGENETIC FACTORS AND THE DURATION, EXTENT AND SEVERITY OF DISEASE. RECENTLY, EPIGENETIC ALTERATIONS, IN PARTICULAR ALTERATIONS IN DNA METHYLATION, HAVE BEEN OBSERVED DURING INFLAMMATION AND INFLAMMATION-ASSOCIATED CARCINOGENESIS. THE MEDIATORS OF THIS, THE SIGNIFICANCE OF THESE CHANGES IN DNA METHYLATION AND THE EFFECT THIS HAS ON GENE EXPRESSION AND THE MALIGNANT TRANSFORMATION OF THE EPITHELIAL CELLS DURING IBD AND CAC ARE DISCUSSED IN THIS REVIEW. THE RECENT ADVANCES IN TECHNOLOGIES TO STUDY GENOME-WIDE DNA METHYLATION AND THE THERAPEUTIC POTENTIAL OF UNDERSTANDING THESE MOLECULAR MECHANISMS ARE ALSO HIGHLIGHTED. 2012 15 6199 44 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 16 1871 36 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 17 2333 31 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 18 2945 28 GENETIC AND EPIGENETIC BASIS OF PSORIASIS PATHOGENESIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE WHOSE PREVALENCE VARIES AMONG DIFFERENT POPULATIONS WORLDWIDE. IT IS A COMPLEX MULTI-FACTORIAL DISEASE AND THE EXACT ETIOLOGY IS LARGELY UNKNOWN. FAMILY BASED STUDIES HAVE INDICATED A GENETIC PREDISPOSITION; HOWEVER THEY CANNOT FULLY EXPLAIN THE DISEASE PATHOGENESIS. IN ADDITION TO GENETIC SUSCEPTIBILITY, ENVIRONMENTAL AS WELL AS GENDER AND AGE RELATED FACTORS WERE ALSO BEEN FOUND TO BE ASSOCIATED. RECENTLY, IMBALANCES IN EPIGENETIC NETWORKS ARE INDICATED TO BE CAUSATIVE ELEMENTS IN PSORIASIS. THE PRESENT KNOWLEDGE OF EPIGENETIC INVOLVEMENT, MAINLY THE DNA METHYLATION, CHROMATIN MODIFICATIONS AND MIRNA DEREGULATION IS SURVEYED HERE. AN INTEGRATED APPROACH CONSIDERING GENETIC AND EPIGENETIC ANOMALIES IN THE LIGHT OF IMMUNOLOGICAL NETWORK MAY EXPLORE THE PATHOGENESIS OF PSORIASIS. 2015 19 551 38 AUTOIMMUNITY AS AN ETIOLOGICAL FACTOR OF CANCER: THE TRANSFORMATIVE POTENTIAL OF CHRONIC TYPE 2 INFLAMMATION. RECENT EPIDEMIOLOGICAL STUDIES HAVE FOUND AN ALARMING TREND OF INCREASED CANCER INCIDENCE IN ADULTS YOUNGER THAN 50 YEARS OF AGE AND PROJECTED A SUBSTANTIAL RISE IN CANCER INCIDENCE OVER THE NEXT 10 YEARS IN THIS AGE GROUP. THIS TREND WAS EXEMPLIFIED IN THE INCIDENCE OF NON-CARDIA GASTRIC CANCER AND ITS DISPROPORTIONATE IMPACT ON NON-HISPANIC WHITE FEMALES UNDER THE AGE OF 50. THE TREND IS CONCURRENT WITH THE INCREASING INCIDENCE OF AUTOIMMUNE DISEASES IN INDUSTRIALIZED COUNTRIES, SUGGESTING A CAUSAL LINK BETWEEN THE TWO. WHILE AUTOIMMUNITY HAS BEEN SUSPECTED TO BE A RISK FACTOR FOR SOME CANCERS, THE EXACT MECHANISMS UNDERLYING THE CONNECTION BETWEEN AUTOIMMUNITY AND CANCER REMAIN UNCLEAR AND ARE OFTEN CONTROVERSIAL. THE LINK HAS BEEN ATTRIBUTED TO SEVERAL MEDIATORS SUCH AS IMMUNE SUPPRESSION, INFECTION, DIET, ENVIRONMENT, OR, PERHAPS MOST PLAUSIBLY, CHRONIC INFLAMMATION BECAUSE OF ITS WELL-RECOGNIZED ROLE IN TUMORIGENESIS. IN THAT REGARD, AUTOIMMUNE CONDITIONS ARE COMMON CAUSES OF CHRONIC INFLAMMATION AND MAY TRIGGER REPETITIVE CYCLES OF ANTIGEN-SPECIFIC CELL DAMAGE, TISSUE REGENERATION, AND WOUND HEALING. ILLUSTRATING THE CONNECTION BETWEEN AUTOIMMUNE DISEASES AND CANCER ARE PATIENTS WHO HAVE AN INCREASED RISK OF CANCER DEVELOPMENT ASSOCIATED WITH GENETICALLY PREDISPOSED INSUFFICIENCY OF CYTOTOXIC T LYMPHOCYTE-ASSOCIATED PROTEIN 4 (CTLA4), A PROTOTYPICAL IMMUNE CHECKPOINT AGAINST AUTOIMMUNITY AND ONE OF THE MAIN TARGETS OF CANCER IMMUNE THERAPY. THE TUMORIGENIC PROCESS TRIGGERED BY CTLA4 INSUFFICIENCY HAS BEEN SHOWN IN A MOUSE MODEL TO BE DEPENDENT ON THE TYPE 2 CYTOKINES INTERLEUKIN-4 (IL4) AND INTERLEUKIN-13 (IL13). IN THIS TYPE 2 INFLAMMATORY MILIEU, CROSSTALK WITH TYPE 2 IMMUNE CELLS MAY INITIATE EPIGENETIC REPROGRAMMING OF EPITHELIAL CELLS, LEADING TO A METAPLASTIC DIFFERENTIATION AND EVENTUALLY MALIGNANT TRANSFORMATION EVEN IN THE ABSENCE OF CLASSICAL ONCOGENIC MUTATIONS. THOSE FINDINGS COMPLEMENT A LARGE BODY OF EVIDENCE FOR TYPE 1, TYPE 3, OR OTHER INFLAMMATORY MEDIATORS IN INFLAMMATORY TUMORIGENESIS. THIS REVIEW ADDRESSES THE POTENTIAL OF AUTOIMMUNITY AS A CAUSAL FACTOR FOR TUMORIGENESIS, THE UNDERLYING INFLAMMATORY MECHANISMS THAT MAY VARY DEPENDING ON HOST-ENVIRONMENT VARIATIONS, AND IMPLICATIONS TO CANCER PREVENTION AND IMMUNOTHERAPY. 2021 20 738 30 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