1 6136 143 THE EPIGENETICS OF MULTIPLE SCLEROSIS AND OTHER RELATED DISORDERS. MULTIPLE SCLEROSIS (MS) IS A DEMYELINATING DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION OF THE CENTRAL NERVOUS SYSTEM (CNS) GRAY AND WHITE MATTER. ALTHOUGH THE CAUSE OF MS IS UNKNOWN, IT IS WIDELY APPRECIATED THAT INNATE AND ADAPTIVE IMMUNE PROCESSES CONTRIBUTE TO ITS PATHOGENESIS. THESE INCLUDE MICROGLIA/MACROPHAGE ACTIVATION, PRO-INFLAMMATORY T-CELL (TH1) RESPONSES AND HUMORAL RESPONSES. ADDITIONALLY, THERE IS EVIDENCE INDICATING THAT MS HAS A NEURODEGENERATIVE COMPONENT SINCE NEURONAL AND AXONAL LOSS OCCURS EVEN IN THE ABSENCE OF OVERT INFLAMMATION. THESE ASPECTS ALSO FORM THE RATIONALE FOR CLINICAL MANAGEMENT OF THE DISEASE. HOWEVER, THE CURRENTLY AVAILABLE THERAPIES TO CONTROL THE DISEASE ARE ONLY PARTIALLY EFFECTIVE AT BEST INDICATING THAT MORE EFFECTIVE THERAPEUTIC SOLUTIONS ARE URGENTLY NEEDED. IT IS APPRECIATED THAT IN THE IMMUNE-DRIVEN AND NEURODEGENERATIVE PROCESSES MS-SPECIFIC DEREGULATION OF GENE EXPRESSIONS AND RESULTING PROTEIN DYSFUNCTION ARE THOUGHT TO PLAY A CENTRAL ROLE. THESE DEVIATIONS IN GENE EXPRESSION PATTERNS CONTRIBUTE TO THE INFLAMMATORY RESPONSE IN THE CNS, AND TO NEURONAL OR AXONAL LOSS. EPIGENETIC MECHANISMS CONTROL TRANSCRIPTION OF MOST, IF NOT ALL GENES, IN NUCLEATED CELLS INCLUDING CELLS OF THE CNS AND IN HAEMATOPOIETIC CELLS. MS-SPECIFIC ALTERATIONS IN EPIGENETIC REGULATION OF GENE EXPRESSION MAY THEREFORE LIE AT THE HEART OF THE DEREGULATION OF GENE EXPRESSION IN MS. AS SUCH, EPIGENETIC MECHANISMS MOST LIKELY PLAY AN IMPORTANT ROLE IN DISEASE PATHOGENESIS. IN THIS REVIEW WE DISCUSS A ROLE FOR MS-SPECIFIC DEREGULATION OF EPIGENETIC FEATURES THAT CONTROL GENE EXPRESSION IN THE CNS AND IN THE PERIPHERY. FURTHERMORE, WE DISCUSS THE APPLICATION OF SMALL MOLECULE INHIBITORS THAT TARGET THE EPIGENETIC MACHINERY TO AMELIORATE DISEASE IN EXPERIMENTAL ANIMAL MODELS, INDICATING THAT SUCH APPROACHES MAY BE APPLICABLE TO MS PATIENTS. 2014 2 4439 47 MOLECULAR GENETIC AND EPIGENETIC BASIS OF MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC IMMUNE-MEDIATED DISEASE OF SPINAL CORD AND BRAIN. THE INITIAL EVENT IN MS OCCURS WHEN ACTIVATED CD4(+) T CELLS IN PERIPHERY EXACERBATES IMMUNE RESPONSES BY STIMULATING IMMUNE CELLS SUCH AS B CELLS, CD8(+) CELLS, MAST CELLS, GRANULOCYTES AND MONOCYTES. THESE PROINFLAMMATORY CELLS PASS BLOOD BRAIN BARRIER BY SECRETING PROINFLAMMATORY CYTOKINES INCLUDING TNF-ALPHA AND INF-(GAMMA) WHICH ACTIVATE ADHESION FACTORS. APCS (ANTIGEN-PRESENTING CELLS) REACTIVATE CD4(+) T CELLS AFTER INFILTRATING THE CNS AND CD4(+) T CELLS PRODUCE CYTOKINES AND CHEMOKINES. THESE PROINFLAMMATORY CYTOKINES AGGRAVATE INFLAMMATION BY INDUCING MYELIN PHAGOCYTOSIS THROUGH MICROGLIA AND ASTROCYTES ACTIVATION. MS IS BELIEVED TO HAVE A MULTIFACTORIAL ORIGIN THAT INCLUDES A COMBINATION OF MULTIPLE GENETIC, ENVIRONMENTAL AND STOCHASTIC FACTORS. ALTHOUGH THE EXACT COMPONENT OF MS RISKS THAT CAN BE EXPLAINED BY THESE FACTORS IS DIFFICULT TO DETERMINE, ESTIMATES BASED ON GENETIC AND EPIDEMIOLOGICAL STUDIES SUGGEST THAT UP TO 60-70 % OF THE TOTAL RISK OF MS MAY BE CONTRIBUTE TO GENETIC FACTORS. IN CONTINUE, FIRSTLY WE PROVIDE AN OVERVIEW OF THE CURRENT UNDERSTANDING OF EPIGENETIC MECHANISMS, AND SO PRESENT EVIDENCE OF HOW THE EPIGENETIC MODIFICATIONS CONTRIBUTE TO INCREASED SUSCEPTIBILITY OF MS. WE ALSO EXPLAIN HOW SPECIFIED EPIGENETIC MODIFICATIONS MAY INFLUENCE THE PATHOPHYSIOLOGY AND KEY ASPECTS OF DISEASE IN MS (DEMYELINATION, REMYELINATION, INFLAMMATION, AND NEURODEGENERATION). FINALLY, WE TEND TO DISCUSS HOW ENVIRONMENTAL FACTORS AND EPIGENETIC MECHANISMS MAY INTERACT TO HAVE AN EFFECT ON MS RISK AND CLINICAL OUTCOME AND RECOMMEND NEW THERAPEUTIC INTERVENTIONS THAT MIGHT MODULATE PATIENTS' EPIGENETIC PROFILES. 2017 3 4536 48 MULTIPLE SCLEROSIS - RISK FACTORS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC AUTOIMMUNOLOGICAL CONDITION OF THE CENTRAL NERVOUS SYSTEM (CNS) AFFECTING MAINLY YOUNG ADULT INDIVIDUALS. THE PREVALENCE RANGES APPROXIMATELY BETWEEN 50 AND 300 PER 100000 INDIVIDUALS. IT IS CHARACTERIZED BY AN INFLAMMATORY PROCESS, DEMYELINATION AND AXONAL LOSS. IMMUNOLOGICAL MECHANISMS RESULTING IN THE DAMAGE TO THE MYELIN SHEATH EFFECTING THEN IN IMPAIRED NERVE IMPULSE CONDUCTION HAVE THE KEY ROLE IN MS PATHOGENESIS. THE ROLE OF INFLAMMATORY FACTORS HAS ALSO BEEN PROVED. HOWEVER, IT HAS NOT BEEN EXPLICITLY SHOWN WHETHER SUCH AN INFLAMMATORY PROCESS IS THE TRIGGERING FACTOR OR SECONDARY TO A YET UNKNOWN INFECTIOUS FACTOR OR A DEGENERATIVE PROCESS OF THE CNS. THEREFORE, RECOGNITION OF THE EPIGENETIC RISK FACTORS, SUCH AS: GEOGRAPHICAL LATITUDE, VITAMIN D LEVEL, HYGIENE HYPOTHESIS, EPSTEIN-BARR VIRUS (EBV) INFECTION AND OTHERS MAY CONTRIBUTE TO BETTER UNDERSTANDING OF THE MECHANISM UNDERLYING MULTIPLE SCLEROSIS. ADDITIONALLY, THEY MAY PROVIDE GUIDELINES FOR MORE EFFICIENT THERAPIES AND BETTER PREVENTION OF THE DISEASE. AIM OF THIS REVIEW IS TO PRESENT MOST CURRENT DATA ON MULTIPLE SCLEROSIS RISK FACTORS, CONSIDERING THOSE LESS KNOWN. 2020 4 6344 34 THE ROLE OF EPIGENETICS IN AGING AND AUTOIMMUNITY. THE DECLINE IN IMMUNOCOMPETENCE WITH AGE IS ACCOMPANIED BY THE INCREASE IN THE INCIDENCE OF AUTOIMMUNE DISEASES. AGING OF THE IMMUNE SYSTEM, OR IMMUNOSENESCENCE, IS CHARACTERIZED BY A DECLINE OF BOTH T AND B CELL FUNCTION, AND PARADOXICALLY THE PRESENCE OF LOW-GRADE CHRONIC INFLAMMATION. THERE IS GROWING EVIDENCE THAT EPIGENETICS, THE STUDY OF INHERITED CHANGES IN GENE EXPRESSION THAT ARE NOT ENCODED BY THE DNA SEQUENCE ITSELF, CHANGES WITH AGING. INTERESTINGLY, EMERGING EVIDENCE SUGGESTS A KEY ROLE FOR EPIGENETICS IN HUMAN PATHOLOGIES, INCLUDING INFLAMMATORY AND NEOPLASTIC DISORDERS. HERE, WE WILL REVIEW THE POTENTIAL MECHANISMS THAT CONTRIBUTE TO THE INCREASE IN AUTOIMMUNE RESPONSES IN AGING. IN PARTICULAR, WE WILL DISCUSS HOW EPIGENETIC ALTERATIONS, ESPECIALLY DNA METHYLATION AND HISTONE ACETYLATION, ARE ACCUMULATED DURING AGING AND HOW THESE EVENTS CONTRIBUTE TO AUTOIMMUNITY RISK. 2010 5 2139 45 EPIGENETIC INSIGHTS INTO MULTIPLE SCLEROSIS DISEASE PROGRESSION. MULTIPLE SCLEROSIS (MS), A CHRONIC INFLAMMATORY DEMYELINATING AND NEURODEGENERATIVE DISEASE OF THE CENTRAL NERVOUS SYSTEM, IS TODAY A LEADING CAUSE OF UNPREDICTABLE LIFELONG DISABILITY IN YOUNG ADULTS. THE TREATMENT OF PATIENTS IN PROGRESSIVE STAGES REMAINS HIGHLY CHALLENGING, ALLUDING TO OUR LIMITED UNDERSTANDING OF THE UNDERLYING PATHOLOGICAL PROCESSES. IN THIS REVIEW, WE PROVIDE INSIGHTS INTO THE MECHANISMS UNDERPINNING MS PROGRESSION FROM A PERSPECTIVE OF EPIGENETICS, THAT REFERS TO STABLE AND MITOTICALLY HERITABLE, YET REVERSIBLE, CHANGES IN THE GENOME ACTIVITY AND GENE EXPRESSION. WE FIRST RECAPITULATE FINDINGS FROM EPIGENETIC STUDIES EXAMINING THE BRAIN TISSUE OF PROGRESSIVE MS PATIENTS, WHICH SUPPORT A CONTRIBUTION OF DNA AND HISTONE MODIFICATIONS IN IMPAIRED OLIGODENDROCYTE DIFFERENTIATION, DEFECTIVE MYELINATION/REMYELINATION AND SUSTAINED NEURO-AXONAL VULNERABILITY. WE NEXT EXPLORE POSSIBILITIES FOR IDENTIFYING FACTORS AFFECTING PROGRESSION USING EASILY ACCESSIBLE TISSUES SUCH AS BLOOD BY COMPARING EPIGENETIC SIGNATURES IN PERIPHERAL IMMUNE CELLS AND BRAIN TISSUE. DESPITE MINOR OVERLAP AT INDIVIDUAL METHYLATION SITES, NEARLY 30% OF ALTERED GENES REPORTED IN PERIPHERAL IMMUNE CELLS OF PROGRESSIVE MS PATIENTS WERE FOUND IN BRAIN TISSUE, JOINTLY CONVERGING ON ALTERATIONS OF NEURONAL FUNCTIONS. WE FURTHER SPECULATE ABOUT THE MECHANISMS UNDERLYING SHARED EPIGENETIC PATTERNS BETWEEN BLOOD AND BRAIN, WHICH LIKELY IMPLY THE INFLUENCE OF INTERNAL (GENETIC CONTROL) AND/OR EXTERNAL (E.G. SMOKING AND AGEING) FACTORS IMPRINTING A COMMON SIGNATURE IN BOTH COMPARTMENTS. OVERALL, WE PROPOSE THAT EPIGENETICS MIGHT SHED LIGHT ON CLINICALLY RELEVANT MECHANISMS INVOLVED IN DISEASE PROGRESSION AND OPEN NEW AVENUES FOR THE TREATMENT OF PROGRESSIVE MS PATIENTS IN THE FUTURE. 2020 6 3703 28 INFLAMMATORY SIGNALLING AS MEDIATOR OF EPIGENETIC MODULATION IN TISSUE-SPECIFIC CHRONIC INFLAMMATION. RECENT SUCCESSES OF THERAPEUTIC INTERVENTION IN CHRONIC INFLAMMATORY DISEASES USING EPIGENETIC MODIFIERS SUCH AS HISTONE DEACETYLASE INHIBITORS AND INHIBITORS OF DNA METHYLATION SUGGEST THAT EPIGENETIC REPROGRAMMING PLAYS A ROLE IN THE AETIOLOGY OF THESE DISEASES. THE EPIGENETIC SIGNATURE OF A GIVEN IMMUNE CELL IS REFLECTED IN THE HISTORY OF MODIFICATIONS FROM DIFFERENT SIGNALS THE CELL HAS BEEN SUBJECTED TO DURING DIFFERENTIATION. LIKE OTHER CELLS, DIFFERENTIATING IMMUNE CELLS ARE DEPENDENT ON A COMPLEX COMBINATION OF INTER- AND INTRACELL SIGNALLING AS WELL AS TRANSCRIPTION MACHINERIES TO MODULATE THEIR EPIGENOMES IN ORDER TO MEDIATE DIFFERENTIATION. DESPITE EXTENSIVE RESEARCH INTO THESE PROCESSES, THE LINK BETWEEN CELLULAR SIGNALLING AND EPIGENETIC MODULATION REMAINS POORLY UNDERSTOOD. HERE, WE REVIEW RECENT PROGRESS AND DISCUSS KEY FACTORS DRIVING EPIGENETIC MODULATION IN CHRONIC INFLAMMATION. 2009 7 5932 43 TARGETING EPIGENETIC REGULATORS FOR INFLAMMATION: MECHANISMS AND INTERVENTION THERAPY. EMERGING EVIDENCE INDICATES THAT RESOLUTION OF INFLAMMATION IS A CRITICAL AND DYNAMIC ENDOGENOUS PROCESS FOR HOST TISSUES DEFENDING AGAINST EXTERNAL INVASIVE PATHOGENS OR INTERNAL TISSUE INJURY. IT HAS LONG BEEN KNOWN THAT AUTOIMMUNE DISEASES AND CHRONIC INFLAMMATORY DISORDERS ARE CHARACTERIZED BY DYSREGULATED IMMUNE RESPONSES, LEADING TO EXCESSIVE AND UNCONTROL TISSUE INFLAMMATION. THE DYSREGULATION OF EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION, POSTTRANSLATIONAL MODIFICATIONS TO HISTONE PROTEINS, AND NONCODING RNA EXPRESSION HAS BEEN IMPLICATED IN A HOST OF INFLAMMATORY DISORDERS AND THE IMMUNE SYSTEM. THE INFLAMMATORY RESPONSE IS CONSIDERED AS A CRITICAL TRIGGER OF EPIGENETIC ALTERATIONS THAT IN TURN INTERCEDE INFLAMMATORY ACTIONS. THUS, UNDERSTANDING THE MOLECULAR MECHANISM THAT DICTATES THE OUTCOME OF TARGETING EPIGENETIC REGULATORS FOR INFLAMMATORY DISEASE IS REQUIRED FOR INFLAMMATION RESOLUTION. IN THIS ARTICLE, WE ELUCIDATE THE CRITICAL ROLE OF THE NUCLEAR FACTOR-KAPPAB SIGNALING PATHWAY, JAK/STAT SIGNALING PATHWAY, AND THE NLRP3 INFLAMMASOME IN CHRONIC INFLAMMATORY DISEASES. AND WE FORMULATE THE RELATIONSHIP BETWEEN INFLAMMATION, CORONAVIRUS DISEASE 2019, AND HUMAN CANCERS. ADDITIONALLY, WE REVIEW THE MECHANISM OF EPIGENETIC MODIFICATIONS INVOLVED IN INFLAMMATION AND INNATE IMMUNE CELLS. ALL THAT MATTERS IS THAT WE PROPOSE AND DISCUSS THE REJUVENATION POTENTIAL OF INTERVENTIONS THAT TARGET EPIGENETIC REGULATORS AND REGULATORY MECHANISMS FOR CHRONIC INFLAMMATION-ASSOCIATED DISEASES TO IMPROVE THERAPEUTIC OUTCOMES. 2022 8 2591 44 EPIGENETICS OF PSORIASIS. PSORIASIS IS A CHRONIC AND RECURRENT INFLAMMATORY SKIN DISEASE, INVOLVING THE RAPID PROLIFERATION AND ABNORMAL DIFFERENTIATION OF KERATINOCYTES AND ACTIVATION OF T CELLS. IT IS GENERALLY ACCEPTED THAT THE CENTRAL PATHOGENESIS OF PSORIASIS IS A T CELL-DOMINANT IMMUNE DISORDER AFFECTED BY MULTIPLE FACTORS INCLUDING GENETIC SUSCEPTIBILITY, ENVIRONMENTAL FACTORS, INNATE AND ADAPTIVE IMMUNE RESPONSES, ETC. HOWEVER, THE EXACT ETIOLOGY IS LARGELY UNKNOWN. IN RECENT YEARS, EPIGENETIC INVOLVEMENTS, SUCH AS THE DNA METHYLATION, CHROMATIN MODIFICATIONS, AND NONCODING RNA REGULATION ARE REPORTED TO BE CRITICAL FOR THE PATHOGENESIS OF PSORIASIS. HOWEVER, THE INTERPLAY BETWEEN THESE FACTORS HAS ONLY RECENTLY BEEN STARTED TO BE UNRAVELED. NOTABLY, INHIBITORS OF ENZYMES THAT WORK IN EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLTRANSFERASES AND HISTONE DEACETYLASES, ARE BEGINNING TO APPEAR IN THE CLINICAL SETTING TO RESTORE NORMAL EPIGENETIC PATTERNS (GENERALI ET AL. IN J AUTOIMMUN 83:51-61, 2017), PROVIDING NOVEL THERAPEUTIC POTENTIAL AS NOVEL TREATMENT TARGETS FOR PSORIASIS. INDEED, MEDICATIONS PREVIOUSLY USED TO TREAT AUTOIMMUNE DISEASES HAVE LATER BEEN DISCOVERED TO EXERT THEIR ACTION VIA EPIGENETIC MECHANISMS. HEREIN, WE REVIEW THE FINDINGS ON EPIGENETICS ASSOCIATED WITH PSORIASIS, AND DISCUSS FUTURE PERSPECTIVES IN THIS FIELD. 2020 9 2070 32 EPIGENETIC CONTROL OF SKIN IMMUNITY. EPIGENETICS HAS BEEN WELL UNDERSTOOD FOR ITS ROLE IN CELL DEVELOPMENT; HOWEVER, IT IS NOW KNOWN TO REGULATE MANY PROCESSES INVOLVED IN IMMUNE CELL ACTIVATION IN A VARIETY OF CELLS. THE SKIN MAINTAINS HOMEOSTASIS VIA CROSSTALK BETWEEN IMMUNE AND NON-IMMUNE CELLS. DISRUPTION OF NORMAL EPIGENETIC REGULATION IN THESE CELLS MAY ALTER THE TRANSCRIPTION OF IMMUNE-REGULATORY FACTORS AND AFFECT THE IMMUNOLOGICAL BALANCE IN THE SKIN. THIS REVIEW SUMMARIZES RECENT EVIDENCE FOR THE EPIGENETIC REGULATION OF SKIN IMMUNITY. MUCH OF WHAT IS KNOWN ABOUT EPIGENETIC INVOLVEMENT IN SKIN IMMUNITY IS ASSOCIATED WITH DNA METHYLATION. THIS REVIEW FOCUSES ON EPIGENETIC REGULATION OF HISTONE MODIFICATION AND CHROMATIN REMODELING AND DESCRIBES THEIR ROLE IN THE TRANSCRIPTIONAL REGULATION OF IMMUNE-REGULATORY FACTORS. WHILE MUCH IS STILL UNKNOWN REGARDING THE REGULATION OF SKIN IMMUNITY VIA HISTONE MODIFICATION OR CHROMATIN REMODELING, THESE PROCESSES MAY UNDERLIE THE PATHOGENESIS OF CHRONIC CUTANEOUS IMMUNE DISORDERS. 2023 10 3123 39 GETTING AN INSIGHT INTO THE COMPLEXITY OF MAJOR CHRONIC INFLAMMATORY AND DEGENERATIVE DISEASES: A POTENTIAL NEW SYSTEMIC APPROACH TO THEIR TREATMENT. AS THE MODERN SOCIETY IS TROUBLED BY MULTI-FACTORIAL DISEASES, RESEARCH HAS BEEN CONDUCTED ON COMPLEX REALITIES INCLUDING CHRONIC INFLAMMATION, CANCER, OBESITY, HIV INFECTION, METABOLIC SYNDROME AND ITS DETRIMENTAL CARDIOVASCULAR COMPLICATIONS AS WELL AS DEPRESSION AND OTHER BRAIN DISORDERS. DETERIORATION OF CRUCIAL HOMEOSTATIC MECHANISMS IN SUCH DISEASES INVARIABLY RESULTS IN ACTIVATION OF INFLAMMATORY MEDIATORS, CHRONIC INFLAMMATION, LOSS IN IMMUNOLOGICAL FUNCTION, INCREASED SUSCEPTIBILITY TO DISEASES, ALTERATION OF METABOLISM, DECREASE OF ENERGY PRODUCTION AND NEURO-COGNITIVE DECLINE. REGULATION OF GENES EXPRESSION BY EPIGENETIC CODE IS THE DOMINANT MECHANISM FOR THE TRANSDUCTION OF ENVIRONMENTAL INPUTS, SUCH AS STRESS AND INFLAMMATION TO LASTING PHYSIOLOGICAL CHANGES. ACUTE AND CHRONIC STRESS DETERMINES DNA METHYLATION AND HISTONE MODIFICATIONS IN BRAIN REGIONS WHICH MAY CONTRIBUTE TO NEURO-DEGENERATIVE DISORDERS. NUCLEAR GLUCOCORTICOIDS RECEPTOR INTERACTS WITH THE EPIGENOMA RESULTING IN A CORTISOL RESISTANCE STATUS ASSOCIATED WITH A DETERIORATION OF THE METABOLIC AND IMMUNE FUNCTIONS. GONADAL STEROIDS RECEPTORS HAVE A SIMILAR CAPACITY TO PRODUCE EPIGENOMIC REORGANIZATION OF CHROMATINE STRUCTURE. EPIGENOMIC-INDUCED REDUCTION IN IMMUNE CELLS TELOMERES LENGTH HAS BEEN OBSERVED IN MANY DEGENERATIVE DISEASES, INCLUDING ALL TYPES OF CANCER. THE FINAL RESULT OF THESE EPIGENETIC ALTERATIONS IS A SERIOUS DAMAGE TO THE NEURO-ENDOCRINE-IMMUNE-METABOLIC ADAPTIVE SYSTEMS. IN THIS STUDY, WE PROPOSE A TREATMENT WITH STEM CELLS DIFFERENTIATION STAGE FACTORS TAKEN FROM ZEBRAFISH EMBRYOS WHICH ARE ABLE TO REGULATE THE GENES EXPRESSION OF NORMAL AND PATHOLOGICAL STEM CELLS IN A DIFFERENT SPECIFIC WAY. 2015 11 5130 35 POSTTRANSCRIPTIONAL GENE REGULATION: NOVEL PATHWAYS FOR GLUCOCORTICOIDS' ANTI-INFLAMMATORY ACTION. POSTTRANSCRIPTIONAL GENE REGULATION (PTR) IS A FUNDAMENTAL BIOLOGICAL PROCESS THAT INTEGRATES WITH THE MASTER TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION, IN WAYS THAT ONLY IN THE LAST DECADE HAVE BEEN INCREASINGLY UNDERSTOOD [1, 2]. WHILE EPIGENETIC AND TRANSCRIPTIONAL EVENTS SHAPE CELL RESPONSE QUALITATIVELY, DECIDING THE PATTERN OF GENE EXPRESSION TO 'SWITCH ON OR OFF' IN RESPONSE TO ENDOGENOUS OR ENVIRONMENTAL TRIGGERS, THE KEY TASK OF PTR IS TO ACT AS A 'RHEOSTAT' AND RAPIDLY ADAPT THE CELLULAR RESPONSE BY PROVIDING THE APPROPRIATE AMPLITUDE AND TIMING TO THE PROTEIN EXPRESSION PATTERNS [3, 4]. THE PIVOTAL ROLE OF THIS MECHANISM COMES TO THE FOREFRONT IN INFLAMMATORY AND IMMUNE RESPONSE, WHERE THE CHANGES IN AMPLITUDE AND DURATION IN THE EXPRESSION OF DANGEROUS AND PROTECTIVE GENES ARE IN DELICATE BALANCE, AND ARE CRITICAL IN DETERMINING EITHER THE SUCCESSFUL RESOLUTION OF THE IMMUNE RESPONSE OR ITS CHRONIC OVEREXPRESSION [5]. THIS BRIEF REVIEW INTRODUCES MEMBERS OF THE MAIN CLASSES OF MOLECULES MEDIATING THE CYTOPLASMIC ARM OF GENE REGULATION, NAMELY RNA-BINDING PROTEINS AND MICRO-RNA (MIRNA), AND SUMMARIZES EXPERIMENTAL DATA THAT UNDERSCORE THE ROLE OF THESE MOLECULES IN THE PATHOPHYSIOLOGY OF CHRONIC INFLAMMATION, AS WELL AS THEIR PROMISING VALUE AS MECHANISMS CONVEYING THE ANTI-INFLAMMATORY EFFECT OF SYNTHETIC GLUCOCORTICOIDS. 2012 12 2532 41 EPIGENETICS IN ATHEROSCLEROSIS AND INFLAMMATION. ATHEROSCLEROSIS IS A MULTIFACTORIAL DISEASE WITH A SEVERE BURDEN ON WESTERN SOCIETY. RECENT INSIGHTS INTO THE PATHOGENESIS OF ATHEROSCLEROSIS UNDERSCORE THE IMPORTANCE OF CHRONIC INFLAMMATION IN BOTH THE INITIATION AND PROGRESSION OF VASCULAR REMODELLING. EXPRESSION OF IMMUNOREGULATORY MOLECULES BY VASCULAR WALL COMPONENTS WITHIN THE ATHEROSCLEROTIC LESIONS IS ACCORDINGLY THOUGHT TO CONTRIBUTE TO THE ONGOING INFLAMMATORY PROCESS. BESIDES GENE REGULATORY PROTEINS (TRANSCRIPTION FACTORS), EPIGENETIC MECHANISMS ALSO PLAY AN ESSENTIAL AND FUNDAMENTAL ROLE IN THE TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION. THESE EPIGENETIC MECHANISMS CHANGE THE ACCESSIBILITY OF CHROMATIN BY DNA METHYLATION AND HISTONE MODIFICATIONS. EPIGENETIC MODULATORS ARE THUS CRITICALLY INVOLVED IN THE REGULATION OF VASCULAR, IMMUNE AND TISSUE-SPECIFIC GENE EXPRESSION WITHIN THE ATHEROSCLEROTIC LESION. IMPORTANTLY, EPIGENETIC PROCESSES ARE REVERSIBLE AND MAY PROVIDE AN EXCELLENT THERAPEUTIC TARGET. THE CONCEPT OF EPIGENETIC REGULATION IS GRADUALLY BEING RECOGNIZED AS AN IMPORTANT FACTOR IN THE PATHOGENESIS OF ATHEROSCLEROSIS. RECENT RESEARCH PROVIDES AN ESSENTIAL LINK BETWEEN INFLAMMATION AND REPROGRAMMING OF THE EPIGENOME. IN THIS REVIEW WE THEREFORE DISCUSS THE BASIS OF EPIGENETIC REGULATION - AND THE CONTRIBUTION THEREOF IN THE REGULATION OF INFLAMMATORY PROCESSES IN GENERAL AND DURING ATHEROSCLEROSIS IN PARTICULAR. MOREOVER WE HIGHLIGHT POTENTIAL THERAPEUTIC INTERVENTIONS BASED ON EPIGENETIC MECHANISMS. 2010 13 2333 37 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 14 6886 33 [ROLE OF EPIGENETIC MODIFICATION IN HIGHER BRAIN DYSFUNCTION AND AGING]. EPIGENETIC MECHANISMS TYPICALLY INVOLVE HERITABLE ALTERATIONS IN CHROMATIN STRUCTURE, WHICH, IN TURN, REGULATE GENE EXPRESSION. FUNDAMENTAL INSIGHTS ABOUT EPIGENETIC HERITABILITY HAVE COME FROM STUDIES OF CELL DIVISION AND DEVELOPMENT. HOWEVER, THERE IS INCREASING EVIDENCE THAT THE REGULATION OF CHROMATIN STRUCTURE THROUGH HISTONE MODIFICATIONS AND DNA METHYLATION MIGHT MEDIATE THE EXPRESSION OF KEY GENES INVOLVED IN ACQUIRED CHRONIC DISORDERS. THIS IDEA IS FASCINATING BECAUSE SIMILAR MECHANISMS ARE USED FOR TRIGGERING AND STORING LONG-TERM MEMORIES AT THE CELLULAR LEVEL DURING, FOR EXAMPLE, HIGHER-BRAIN DYSFUNCTION, STRESS DISEASE, DRUG DEPENDENCE, AGING, AND CHRONIC PAIN. THIS REVIEW WILL EXPLORE THE MOST CURRENT ISSUES IN THE FIELD OF EPIGENETICS, WITH A FOCUS ON NEXT LEVELS OF TRANSCRIPTIONAL MECHANISMS UNDERLYING AGING, ENRICHED ENVIRONMENT AND DRUG ADDICTION. EPIGENETIC MECHANISMS, WHICH ARE KEY CELLULAR AND MOLECULAR PROCESSES THAT INTEGRATE DIVERSE ENVIRONMENTAL STIMULI TO EXERT POTENT AND OFTEN LONG-LASTING CHANGES IN GENE EXPRESSION THROUGH THE REGULATION OF CHROMATIN STRUCTURE, CONTRIBUTE TO TRANSCRIPTIONAL AND BEHAVIORAL CHANGES. 2012 15 6199 43 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 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 17 5410 37 REGULATION OF ADAPTIVE IMMUNE CELLS BY SIRTUINS. IT IS NOW WELL-ESTABLISHED THAT THE PATHWAYS THAT CONTROL LYMPHOCYTE METABOLISM AND FUNCTION ARE INTIMATELY LINKED, AND CHANGES IN LYMPHOCYTE METABOLISM CAN INFLUENCE AND DIRECT CELLULAR FUNCTION. INTERESTINGLY, A NUMBER OF RECENT ADVANCES INDICATE THAT LYMPHOCYTE IDENTITY AND METABOLISM IS PARTIALLY CONTROLLED VIA EPIGENETIC REGULATION. EPIGENETIC MECHANISMS, SUCH AS CHANGES IN DNA METHYLATION OR HISTONE ACETYLATION, HAVE BEEN FOUND TO ALTER IMMUNE FUNCTION AND PLAY A ROLE IN NUMEROUS CHRONIC DISEASE STATES. THERE ARE SEVERAL ENZYMES THAT CAN MEDIATE EPIGENETIC CHANGES; OF PARTICULAR INTEREST ARE SIRTUINS, PROTEIN DEACETYLASES THAT MEDIATE ADAPTIVE RESPONSES TO A VARIETY OF STRESSES (INCLUDING CALORIE RESTRICTION AND METABOLIC STRESS) AND ARE NOW UNDERSTOOD TO PLAY A SIGNIFICANT ROLE IN IMMUNITY. THIS REVIEW WILL FOCUS ON RECENT ADVANCES IN THE UNDERSTANDING OF HOW SIRTUINS AFFECT THE ADAPTIVE IMMUNE SYSTEM. THESE PATHWAYS ARE OF SIGNIFICANT INTEREST AS THERAPEUTIC TARGETS FOR THE TREATMENT OF AUTOIMMUNITY, CANCER, AND TRANSPLANT TOLERANCE. 2019 18 3540 35 IMMUNE-DERIVED CYTOKINES IN THE NERVOUS SYSTEM: EPIGENETIC INSTRUCTIVE SIGNALS OR NEUROPATHOGENIC MEDIATORS? THE INVESTIGATION OF THE EFFECTS OF INFLAMMATORY CYTOKINES (IC) ON THE GROWTH AND DIFFERENTIATION OF NEURAL CELLS HAS PROVIDED NEW INSIGHTS ON THE ROLE OF SUCH SOLUBLE MEDIATORS IN NERVOUS SYSTEM DEVELOPMENT AND/OR PLASTIC REMODELING AS WELL AS IN THE PATHOGENESIS OF INFLAMMATORY NEURODEGENERATIVE DISORDERS, WHICH ARE CHARACTERIZED BY CHRONIC IC DYSREGULATION IN THE CENTRAL NERVOUS SYSTEM (CNS). THUS, THE STUDY OF THE INTERACTION BETWEEN CNS AND IMMUNE-DERIVED SOLUBLE SIGNALS IN PHYSIOLOGICAL OR PATHOLOGICAL CONDITIONS IS OF INCREASING INTEREST. THIS REVIEW FIRST DISCUSSES EXPERIMENTAL EVIDENCE SUPPORTING THE INSTRUCTIVE/PERMISSIVE ROLE OF IMMUNE-DERIVED CYTOKINES ON CNS DEVELOPMENT AND PLASTICITY. NEXT, WE FOCUS ON HUMAN NEUROLOGICAL DISEASE STATES SUCH AS MULTIPLE SCLEROSIS AND THE NEURODEGENERATION ASSOCIATED TO THE ACQUIRED IMMUNE DEFICIENCY SYNDROME IN WHICH DIFFERENT INFLAMMATORY CYTOKINES HAVE BEEN PROPOSED AS POTENTIAL NEUROPATHOGENIC MEDIATORS. 1999 19 6255 33 THE MICROBIOTA AND EPIGENETIC REGULATION OF T HELPER 17/REGULATORY T CELLS: IN SEARCH OF A BALANCED IMMUNE SYSTEM. IMMUNE CELLS NOT ONLY AFFECT TISSUE HOMEOSTASIS AT THE SITE OF INFLAMMATION BUT ALSO EXERT SYSTEMIC EFFECTS CONTRIBUTING TO MULTIPLE CHRONIC CONDITIONS. RECENT EVIDENCE CLEARLY SUPPORTS AN ALTERED T HELPER 17/REGULATORY T CELL (TH17/TREG) BALANCE LEADING TO THE DEVELOPMENT AND PROGRESSION OF INFLAMMATORY DISEASES THAT NOT ONLY AFFECT THE GASTROINTESTINAL TRACT BUT ALSO HAVE WHOLE-BODY MANIFESTATIONS, INCLUDING INSULIN RESISTANCE. EPIGENETIC MECHANISMS ARE AMENABLE TO BOTH ENVIRONMENTAL AND CIRCULATING FACTORS AND CONTRIBUTE TO DETERMINING THE T CELL LANDSCAPE. THE RECENTLY IDENTIFIED PARTICIPATION OF THE GUT MICROBIOTA IN THE REMODELING OF THE EPIGENOME OF IMMUNE CELLS HAS TRIGGERED A PARADIGM SHIFT IN OUR UNDERSTANDING OF THE ETIOLOGY OF VARIOUS INFLAMMATORY DISEASES AND OPENED NEW PATHS TOWARD THERAPEUTIC STRATEGIES. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE CONTRIBUTION OF THE TH17/TREG BALANCE IN THE DEVELOPMENT AND PROGRESSION OF INFLAMMATORY BOWEL DISEASES AND METABOLIC DISEASES. WE DISCUSS THE INVOLVEMENT OF EPIGENETIC MECHANISMS IN THE REGULATION OF T CELL FUNCTION IN THE PARTICULAR CONTEXT OF DYSBIOSIS. FINALLY, WE EXAMINE THE POTENTIAL FOR NUTRITIONAL INTERVENTIONS AFFECTING THE GUT MICROBIOTA TO RESHAPE THE T CELL EPIGENOME AND ADDRESS THE INFLAMMATORY COMPONENT OF VARIOUS DISEASES. 2017 20 6131 34 THE EPIGENETIC REGULATION OF WOUND HEALING. SIGNIFICANCE: EPIGENETIC REGULATORY MECHANISMS ARE ESSENTIAL FOR EPIDERMAL HOMEOSTASIS AND CONTRIBUTE TO THE PATHOGENESIS OF MANY SKIN DISEASES, INCLUDING SKIN CANCER AND PSORIASIS. HOWEVER, WHILE THE EPIGENETIC REGULATION OF EPIDERMAL HOMEOSTASIS IS NOW BECOMING ACTIVE AREA OF RESEARCH, THE EPIGENETIC MECHANISMS CONTROLLING THE WOUND HEALING RESPONSE REMAIN RELATIVELY UNTOUCHED. RECENT ADVANCES: SUBSTANTIAL PROGRESS ACHIEVED WITHIN THE LAST TWO DECADES IN UNDERSTANDING EPIGENETIC MECHANISMS CONTROLLING GENE EXPRESSION ALLOWED DEFINING SEVERAL LEVELS, INCLUDING COVALENT DNA AND HISTONE MODIFICATIONS, ATP-DEPENDENT AND HIGHER-ORDER CHROMATIN CHROMATIN REMODELING, AS WELL AS NONCODING RNA- AND MICRORNA-DEPENDENT REGULATION. RESEARCH PERTAINED OVER THE LAST FEW YEARS SUGGESTS THAT EPIGENETIC REGULATORY MECHANISMS PLAY A PIVOTAL ROLE IN THE REGULATION OF SKIN REGENERATION AND CONTROL AN EXECUTION OF REPARATIVE GENE EXPRESSION PROGRAMS IN BOTH SKIN EPITHELIUM AND MESENCHYME. CRITICAL ISSUES: EPIGENETIC REGULATORS APPEAR TO BE INHERENTLY INVOLVED IN THE PROCESSES OF SKIN REPAIR, AND ARE ABLE TO DYNAMICALLY REGULATE KERATINOCYTE PROLIFERATION, DIFFERENTIATION, AND MIGRATION, TOGETHER WITH INFLUENCING DERMAL REGENERATION AND NEOANGIOGENESIS. THIS IS ACHIEVED THROUGH A SERIES OF COMPLEX REGULATORY MECHANISMS THAT ARE ABLE TO BOTH STIMULATE AND REPRESS GENE ACTIVATION TO TRANSIENTLY ALTER CELLULAR PHENOTYPE AND BEHAVIOR, AND INTERACT WITH GROWTH FACTOR ACTIVITY. FUTURE DIRECTIONS: UNDERSTANDING THE MOLECULAR BASIS OF EPIGENETIC REGULATION IS A PRIORITY AS IT REPRESENTS POTENTIAL THERAPEUTIC TARGETS FOR THE TREATMENT OF BOTH ACUTE AND CHRONIC SKIN CONDITIONS. FUTURE RESEARCH IS, THEREFORE, IMPERATIVE TO HELP DISTINGUISH EPIGENETIC MODULATING DRUGS THAT CAN BE USED TO IMPROVE WOUND HEALING. 2014